Electrical muscle controller

ABSTRACT

A method of modifying the force of contraction of at least a portion of a heart chamber, including providing a subject having a heart, comprising at least a portion having an activation, and applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, which causes the force of contraction to be increased by a least 5%.

RELATED APPLICATIONS

The present application is a continuation of commonly assigned U.S.patent application Ser. No. 11/550,560, filed Oct. 18, 2006, which is acontinuation of commonly assigned U.S. patent application Ser. No.10/866,213, filed Jun. 10, 2004 now U.S. Pat. No. 7,167,748, which is acontinuation of commonly assigned U.S. patent application Ser. No.10/001,710, filed Oct. 31, 2001 now U.S. Pat. No. 7,062,318, which is acontinuation of U.S. patent application Ser. No. 09/723,989, filed Nov.28, 2000 now U.S. Pat. No. 6,330,476, which is a continuation ofcommonly assigned U.S. patent application Ser. No. 09/101,723, filedAug. 13, 1998, now U.S. Pat. No. 6,317,631, which is a National Phase ofPCT Patent Application No. PCT/IL97/00012, filed Jan. 8, 1997, which isrelated to the following U.S. and Israeli applications, the disclosuresof which are also incorporated herein by reference: U.S. Provisionalpatent application No. 60/009,769, filed Jan. 11, 1996, Israel patentapplication No. 116,699, filed Jan. 8, 1996, U.S. Provisional patentapplication No. 60/011,117, filed Feb. 5, 1996, Israeli patentapplication No. 119,261, filed Sep. 17, 1996, U.S. ProvisionalApplication No. 60/026,392, filed Sep. 16, 1996, and U.S. patentapplication Ser. No. 08/595,365, filed Feb. 1, 1996, now U.S. Pat. No.5,738,096. The disclosures of all aforementioned patents and patentapplications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to cardiac muscular control, in particularcontrol using non-excitatory electrical signals.

BACKGROUND OF THE INVENTION

The heart is a muscular pump whose mechanical activation is controlledby electrical stimulation generated at a right atrium and passed to theentire heart. In a normal heart, the electrical stimulation that drivesthe heart originates as action potentials in a group of pacemaker cellslying in a sino-atrial (SA) node in the right atrium. These actionpotentials then spread rapidly to both right and left atria. When theaction potential reaches an unactivated muscle cell, the celldepolarizes (thereby continuing the spread of the action potential) andcontacts. The action potentials then enter the heart's conduction systemand, after a short delay, spread through the left and right ventriclesof the heart. It should be appreciated that activation signals arepropagated within the heart by sequentially activating connected musclefibers. Each cardiac muscle cell generates a new action potential forstimulating the next cell, after a short delay and in response to theactivation signal which reaches it. Regular electrical currents can beconducted in the heart, using the electrolytic properties of the bodyfluids, however, due the relatively large resistance of the heartmuscle, this conduction cannot be used to transmit the activationsignal.

In a muscle cell of a cardiac ventricle, the resting potential acrossits cellular membrane is approximately −90 mV (millivolts) (the insideis negatively charged with respect to the outside). FIG. 1A shows atransmembrane action potential of a ventricle cardiac muscle cell duringthe cardiac cycle. When an activation signal reaches one end of thecell, a depolarization wave rapidly advances along the cellular membraneuntil the entire membrane is depolarized, usually to approximately +20mV (23). Complete depolarization of the cell membrane occurs in a veryshort time, about a few millisecond. The cell then rapidly (not as rapidas the depolarization) depolarizes by about 10 mV. After the rapiddepolarization, the cell slowly repolarizes by about 20 mV over a periodof approximately 200-300 msec (milliseconds), called the plateau (25).It is during the plateau that the muscle contraction occurs. At the endof the plateau, the cell rapidly repolarizes (27) back to its restingpotential (21). Different cardiac muscle cells have different electricalcharacteristics in particular, cells in an SA node do not have asubstantial plateau and do not reach as low a resting potential asventricular cells.

In the following discussion, it should be appreciated that the exactmechanisms which govern action potentials and ionic pumps and channelsare only partly known. Many theories exist and the field in is aconstant state of flux.

The electrical activity mirrors chemical activity in a cell. Beforedepolarization (at resting), the concentration of sodium ions inside thecell is about one tenth the concentration in the interstitial fluidoutside the cell. Potassium ions are about thirty-five times moreconcentrated inside the cell than outside. Calcium ions are over tenthousand times more concentrated outside the cell than inside the cell.These concentration differentials are maintained by the selectivepermeability of the membrane to different ions and by ionic pumps in themembrane of the cell which continuously pump sodium and calcium ions outand potassium ions in. One result of the concentration differencesbetween the cell and the external environment is a large negativepotential inside the cell about 90 mV as indicated above.

When a portion of the cell membrane is depolarized, such as by an actionpotential, the depolarization wave spreads along the membrane. This wavecauses a plurality of voltage-gated sodium channels to open. An influxof sodium through these channels rapidly changes the potential of themembrane from negative to positive (23 in FIG. 1A). Once the voltagebecomes less negative, these channels begin to close, and do not openuntil the cell is again depolarized. It should be noted that the sodiumchannels must be at a negative voltage of at least a particular value inorder to be primed for reopening. Thus, these channels cannot be openedby an activation potential before the cell has sufficiently repolarized.In most cells, the sodium channels usually close more gradually thanthey open. After the rapid depolarization, the membrane suns a fastrepolarization process. The mechanism for the fast repolarization is notfully understood, although closing of the sodium channels appears to bean important factor. Following a short phase of rapid repolarization, arelatively long period (200-300 msec) of slow repolarization term theplateau stage (25 in FIG. 1A) occurs. During the plateau it is notbelieved to be possible to initiate another action potential in thecell, because the sodium channels are inactivated.

Two mechanisms appear to be largely responsible for the long duration ofthe plateau, an inward current of calcium ions and an outward current ofpotassium ions. Both currents flow with their concentration gradients,across the membrane. The net result is that the two types of currentelectrically subtract from each other. In general, the flow of potassiumand calcium is many times slower than the flow of the sodium, which isthe reason why the plateau lasts so long. According to some theories,the potassium channels may also open as a result of the actionpotential, however, the probability of a potassium channel opening isdependent on the potential. Thus, many channels open only after thedepolarization of the cell is under way or completed. Possibly, at leastsome of the potassium channels are activated by the calcium ions. Inaddition, some of the potassium channels are triggered by therepolarization of the membrane. The membrane permeability to potassiumgradually increases, following its drop during the rapid depolarization(23). The calcium channels also conduct sodium back into the cell, whichhelps extend the plateau duration.

The inward calcium current during the normal cardiac action potentialcontributes to the action potential plateau and is also involved in thecontractions (directly and/or indirectly) in the cardiac muscle cells.In a process termed calcium induced calcium release, the inward currentof calcium induces the release of calcium ions stored in intracellularcalcium stores (probably the sacroplasmic reticulum). The existence andimportance of a physical link between the reticulum and the calciumchannels in cardiac muscle is unclear. However, the response curve ofthese calcium stores may be bell-shaped, so that too great an influx ofcalcium may reduce the amount of available calcium relative to amountmade available by a smaller influx.

In single cells and in groups of cells, time is required for cells torecover partial and full excitability during the repolarization process.While the cell is repolarizing (25, 27 in FIG. 1A), it enters a state ofhyper polarization, during which the cell cannot be stimulated again tofire a new action potential. This state is called the refractory period.The refractory period is divided into two parts. During an absoluterefractory period, the cell cannot be re-excited by an outside stimulus,regardless of the voltage level of the stimulus. During a relativerefractory period, a much larger than usual stimulus signal is requiredto cause the cell to fire a new action potential. The refractory stateis probably caused by the sodium channels requiring priming by anegative voltage, so the cell membrane cannot depolarize by flow ofsodium ions until it is sufficiently repolarized. Once the cell returnsto its resting potential (21), the cell may be depolarized again.

In an experimental methodology called voltage clamping, an electricalpotential is maintained across at least a portion of a cell membrane tostudy the effects of voltage on ionic channels, ionic pumps and on thereactivity of the cell.

It is known that by applying a positive potential across the membrane, acell may be made more sensitive to a depolarization signal. Some cellsin the heart, such as the cells in the SA node (the natural pacemaker ofthe heart) have a resting potential of about −55 mV. As a result, theirvoltage-gated sodium channels are permanently inactivated and thedepolarization stage (23) is slower than in ventricular cells (ingeneral, the action potential of an SA node cell is different from thatshown in FIG. 1A). However, cells in the SA node have a built-in leakagecurrent, which causes a self-depolarization of the cell on a periodicbasis. In general, it appears that when the potential of a cell staybelow about −60 mV for a few msec, the voltage-gated sodium channels areblocked. Applying a negative potential across its membrane make a cellless sensitive to depolarization and also hyperpolarizes the cellmembrane, which seems to reduce conduction velocity.

In modern cardiology many parameters of the heart's activation can becontrolled. Pharmaceuticals can be used to control the conductionvelocity, excitability, contractility and duration of the refractoryperiods in the heart. These pharmaceuticals may be used to treatarrhythmias and prevent fibrillations. A special kind of control can beachieved using a pacemaker. A pacemaker is an electronic device which istypically implanted to replace the heart's electrical excitation systemor to bypass a blocked portion of the conduction system. In some typesof pacemaker implantation, portions of the heart's conduction system,for example an atrial-ventricle (AV) node, must be ablated in order forthe pacemaker to operate correctly.

Another type of cardiac electronic device is a defibrillator. As an endresult of many diseases, the heart may become more susceptible tofibrillation, in which the activation of the heart is substantiallyrandom. A defibrillator senses this randomness and resets the heart byapplying a high voltage impulse(s) to the heart.

Pharmaceuticals are generally limited in effectiveness in that theyaffect both healthy and diseased segments of the heart, usually, with arelatively low precision. Electronic pacemakers, are further limited inthat they are invasive, generally require destruction of heart tissueand are not usually optimal in their effects. Defibrillators havesubstantially only one limitation. The act of defibrillation is verypainful to the patient and traumatic to the heart.

“Electrical Stimulation of Cardiac Myoctes,” by Ravi Ranjan and NitishV. Thakor, in Annals of Biomedical Engineering, Vol. 23, pp. 812-821,published by the Biomedical Engineering Society, 1995, the disclosure ofwhich is incorporated herein by reference, describes several experimentsin applying electric fields to cardiac muscle cells. These experimentswere performed to test theories relating to electrical defibrillation,where each cell is exposed to different strengths and different relativeorientations of electric fields. One result of these experiments was thediscovery that if a defibrillation shock is applied duringrepolarization, the repolarization time is extended. In addition, it wasreported that cells have a preferred polarization. Cardiac muscle cellstend to be more irregular at one end than at the other. It is theorizedin the article, that local “hot spots” of high electrical fields aregenerated at these irregularities and that these “hot spots” are thesites of initial depolarization within the cell, since it is at thesesites that the threshold for depolarization is first reached. Thistheory also explains another result, namely that cells are moresensitive to electric fields in their longitudinal direction than intheir transverse direction, since the irregularities are concentrated atthe cell ends. In addition, the asymmetric irregularity of the cells mayexplain results which showed a preferred polarity of the appliedelectric field.

The electrical activation of skeleton muscle cells is similar to that ofcardiac cells in that a depolarization event induces contraction ofmuscle fibers. However, skeleton muscle is divided into isolated musclebundles, each of which is individually enervated by action potentialgenerating nerve cells. Thus, the effect of an action potential islocal, while in a cardiac muscle, where all the muscle cells areelectrically connected, an action potential is transmitted to the entireheart from a single loci of action potential generation. In addition,the chemical aspects of activation of skeletal muscle is somewhatdifferent from those of cardiac muscle.

“Muscle Recruitment with Infrafascicular Electrodes”, by Nicola Nanniniand Kenneth Horch, IEEE Transactions on Biomedical Engineering Vol. 38,No. 8, pp. 769-776, August 1991, the disclosure of which is incorporatedherein by reference, describes a method of varying the contractile forceof skeletal muscles, by “recruiting” varying number of muscle fibers. Inrecruiting, the contractile force of a muscle is determined by thenumber of muscle fibers which are activated by a stimulus.

However, it is generally accepted that cardiac muscle fibers function asa syncytium such that each and every cell contracts at each beat. Thus,there are no cardiac muscles fibers available for recruitment. See forexample, “Excitation Contraction Coupling and Cardiac ContractileForce”, by Donald M. Bers, Chapter 2, page 17, Kluwer Academic, 1991,the disclosure of which is incorporated herein by reference. Thiscitation also states that in cardiac muscle cells, contractile force isvaried in large part by changes in peak calcium.

“Effect of Field Stimulation on Cellular Repolarization in RabbitMyocardium”, by Stephen B. Knisley, William M. Smith and Raymond E.Ideker, Circulation Research Vol. 70, No. 4, pp. 707-715, April 1992,the disclosure of which is incorporated herein by reference, describesthe effect of an electrical field on rabbit myocardium. In particular,this article describes prolongation of an action potential as a resultof a defibrillation shock and ways by which this effect can causedefibrillation to fail. One hypothesis is that defibrillation affectscardiac cells by exciting certain cells which are relatively lessrefractory than others and causes the excited cells to generate a newaction potential, effectively increasing the depolarization time.

“Optical Recording in the Rabbit Heart Show That Defibrillation StrengthShocks Prolong the Duration of Depolarization and the RefractoryPeriod”, by Stephen M. Dillon, Circulation Research, Vol. 69, No. 3, pp.842-856, September, 1991, the disclosure of which is incorporated hereinby reference, explains the effect of prolonged repolarization as causedby the generation of a new action potential in what was thought to berefractory tissue as a result of the defibrillation shock. This articlealso proves experimentally that such an electric shock does not damagethe cardiac muscle tissue and that the effect of a second actionpotential is not due to recruitment of previously unactivated musclefibers. It is hypothesized in this article that the shocks hyperpolarizeportions of the cellular membrane and thus reactivate the sodiumchannels. In the experiments described in this article, the activity ofcalcium channels is blocked by the application of methoxy-verapamil.

Electrical Resistances of Interstitial and Microvascular Space asDeterminants of the Extracellular Electrical field and Velocity ofPropagation in Ventricular Myocardium”, by Johannes Fleischhauer, LillyLehmann and Andre G. Kleber, Circulation, Vol. 92, No. 3, pp. 587-594,Aug. 1, 1995, the disclosure of which is incorporated herein byreference, describes electrical conduction characteristics of cardiacmuscle.

“Inhomogeneity of Cellular Activation Time and Vmax in Normal MyocardialTissue Under Electrical Field Stimulation”, by Akihiko Taniguchi, JunjiToyama, Itsuo Kodama, Takafumi Anno, Masaki Shirakawa and Shiro Usui,American Journal of Physiology, Vol. 267 (Heart Circulation Physiology,Vol. 36), pp. H694-H705, 1994, the disclosure of which is incorporatedherein by reference, describes various interactions betweenelectro-tonic currents and action potential upstrokes.

“Effect of Light on Calcium Transport in Bull Sperm Cells”, by R.Lubart, H. Friedmann, T. Levinshal, R. Lavie and H. Breitbart, Journalof Photochemical Photobiology B, Vol. 14, No. 4, pp. 337-341, Sep. 12,1992, the disclosure of which is incorporated herein by reference,describes an effect of light on bull sperm cells, in which laser lightincreases the calcium transport in these cells. It is also known thatlow level laser light affects calcium transport in other types of cells,for example as described in U.S. Pat. No. 5,464,436, the disclosure ofwhich is incorporated herein by reference.

The ability of electro-magnetic radiation to affect calcium transport incardiac myocytes is well documented. Loginov V A, “Accumulation ofCalcium Ions in Myocardial Saroplasmic Reticulum of Restrained RatsExposed to the Pulsed Electromagnetic Field”, in Aviakosm Ekolog Med,Vol. 26, No. 2, pp. 49-51, March-April, 1992, the disclosure of which isincorporated herein by reference, describes an experiment in which ratswere exposed to a 1 H field of between 6 and 24 mTesla. After one month,a reduction of 33 percent in the velocity of calcium accumulation wasobserved. After a second month, the accumulation velocity was back tonormal, probably due to an adaptation mechanism.

Schwartz J L, House D E and Mealing G A, in “Exposure of Frog Hearts toCW or Amplitude-Modulated VHF Fields: Selective Efflux of Calcium Ionsat 16 Hz”, Bioelectromagnetics, Vol. 11, No. 4, pp. 349-358, 1990, thedisclosure of which is incorporated herein by reference, describes anexperiment in which the efflux of calcium ions in isolated frog heartswas increased by between 18 and 21% by the application of a 16 Hzmodulated VHF electromagnetic field.

Lindstrom E, Lindstrom P, Berglund A, Lundgren E and Mild K H, in“Intracellular Calcium Oscillations in a T-cell Line After Exposure toExtremely-Low-Frequency Magnetic Fields with Variable Frequencies andFlux Densities”, Bioelectromagnetics, Vol. 16, No. 1, pp. 41-47, 1995,the disclosure of which is incorporated herein by reference, describesan experiment in which magnetic fields, at frequency between 5 and 100Hz (Peak at 50 Hz) and with intensities of between 0.04 and 0.15 mTeslaaffected calcium ion transport in T-cells.

Loginov V A, Gorbatenkova N V and Klimovitskii Via, in “Effects of anImpulse Electromagnetic Field on Calcium Ion Accumulation in theSarcoplasmatic Reticulum of the Rat Myocardium”, Kosm Biol Aviakosm Med,Vol. 25, No. 5, pp. 51-53, September-October, 1991, the disclosure ofwhich is incorporated herein by reference, describes an experiment inwhich a 100 minute exposure to a 1 msec impulse, 10 Hz frequency and1-10 mTesla field produced a 70% inhibition of calcium transfer acrossthe sarcoplasmic reticulum. The effect is hypothesized to be associatedwith direct inhibition of Ca-ATPase.

It should be noted that some researchers claim that low frequencymagnetic fields do NOT have the above reported effects. For example,Coulton L A and Barker A T, in “Magnetic Fields and IntracellularCalcium: Effects on Lymphocytes Exposed to Conditions for ‘CyclotronResonance’”, Phys Med Biol, Vol. 38, No. 3, pp. 347-360, March, 1993,the disclosure of which is incorporated herein by references, exposedlymphocytes to radiation at 16 and 50 Hz, for a duration of 60 minutesand failed to detect any changes in calcium concentration.

Pumir A, Plaza F and Krinsky VI, in “Control of Rotating Waves inCardiac Muscle: Analysis of the Effect of Electric Fields”, Proc R SocLond B Biol Sci, Vol. 257, No. 1349, pp. 129-34, Aug. 22, 1994, thedisclosure of which is incorporated herein by reference, describes thatan application of an external electric field to cardiac muscle affectsconduction velocity by a few percent. This effect is due to thehyperpolarization of one end of muscle cells and a depolarization of theother end of the cell. In particular, an externally applied electricfield favors propagation antiparallel to it. It is suggested in thearticle to use this effect on conduction velocity to treat arrhythmiasby urging rotating waves, which are the precursors to arrhythmias, todrift sideways to non-excitable tissue and die.

“Control of Muscle Contractile Force Through Indirect High-FrequencyStimulation”, by M. Sblomonow, E. Eldred, J. Lyman and J. Foster,American Journal of Physical Medicine, Vol. 62, No. 2, pp. 71-82, April1983, the disclosure of which is incorporated herein by reference,describes a method of controlling skeletal muscle contraction by varyingvarious parameters of a 500 Hz pulse of electrical stimulation to themuscle.

“Biomedical Engineering Handbook”, ed. Joseph D. Bronzino, chapter 82.4,page 1288, IEEE press/CRC press, 1995, describes the use of preciselytimed subthreshold stimuli, simultaneous stimulation at multiple sitesand pacing with elevated energies at the site of a tachycardia foci, toprevent tachycardia. However, none of these methods had proven practicalat the time the book was written. In addition a biphasic defibrillationscheme is described and it is theorized that biphasic defibrillationschemes are more effective by virtue of a larger voltage change when thephase changes or by the biphasic waveform causing hyperpolarization oftissue and reactivation of sodium channels.

“Subthreshold Conditioning Stimuli Prolong Human VentricularRefractoriness”, Windle J R, Miles W M, Zipes D P and Prystowsky E N,American Journal of Cardiology, Vol. 57, No. 6, pp. 381-386, February,1986, the disclosure of which is incorporated herein by reference,describes a study in which subthreshold stimuli were applied before apremature stimulus and effectively blocked the premature stimulus fromhaving a pro-arrhythmic effect by a mechanism of increasing therefractory period of right ventricular heart tissue.

“Ultrarapid Subthreshold Stimulation for Termination of AtrioventricularNode Reentrant Tachycardia”, Fromer M and Shenasa M, Journal of theAmerican Collage of Cardiology, Vol, 20, No, 4, pp. 879-883, October,1992, the disclosure of which is incorporated herein by reference,describes a study in which trains of subthreshold stimuli were appliedasynchronously to an area net a reentry circuit and thereby terminatedthe arthythmia. Subthreshold stimuli were described as having both aninhibitory and a facilitating effect on conduction. In addition,subthreshold stimuli are described as reducing the threshold ofexcitability, possibly even causing an action potential.

“Inhibition of Premature Ventricular Extrastimuli by SubthresholdConditioning Stimuli”, Skale B, Kallok M J, Prystowsky E N, Gill R M andZipes D P, Journal of the American Collage of Cardiology, Vol. 6, No. 1,pp. 133-140, July, 1985, the disclosure of which is incorporated hereinby reference, describes an animal study in which a train of 1 msecduration pulses were applied to a ventricle 2 msec before a prematurestimuli, inhibited the response to the premature stimuli, with a highfrequency train delaying the response for a much longer amount of time(152 msec) than a single pulse (20 msec). The delay between the pacingof the ventricle and the pulse train was 75 msec. However, thesubthreshold stimuli only had this effect when delivered to the samesite as the premature stimulus. It is suggested to use a subthresholdstimuli in to prevent or terminate tachycardias, however, it is notedthat this suggestion is restrained by the spatial limitation of thetechnique.

“The Phase of Supernormal Excitation in Relation to the Strength ofSubthreshold Stimuli“, Yokoyama M, Japanese Heart Journal, Vol. 17, No,3, pp. 35-325, May, 1976, the disclosure of which is incorporated hereinby reference, describes the effect of varying the amplitude of asubthreshold stimuli on supernormal excitation. When the amplitude ofthe stimuli was increase the supernormal excitation phase increased inlength.

SUMMARY OF THE INVENTION

It is an object of some aspects of the present invention to provide amethod of locally controlling the electrical and/or mechanical activityof cardiac muscle cells, in situ. Preferably, continuous control isapplied. Alternatively, discrete control is applied. Further preferably,the control may be varied between cardiac cycles. One example ofelectrical control is shortening the refractory period of a muscle fiberby applying a negative voltage to the outside of the cell. The cell mayalso be totally blocked from reacting by maintaining a sufficientlypositive voltage to the outside of the cell, so that an activationsignal fails to sufficiently depolarize the cellular membrane. Oneexample of mechanical control includes increasing or decreasing bestrength of contraction and the duration of the contraction. This may beachieved by extending or shortening the plateau and/or the actionpotential duration by applying non-excitatory voltage potentials acrossthe cell. The increase in strength of contraction may include anincrease in peak force of contraction attained by muscle fibers, may bean increase in an average force of contraction, by synchronization ofcontraction of individual fibers or may include hanging the timing ofthe peak strength.

It should be appreciated that some aspects of the present invention aredifferent from both pacemaker operation and defibrillator operation. Apacemaker exerts excitatory electric fields for many cycles, while adefibrillator does not repeat its applied electric field for manycycles, due to the disruptive effect of the defibrillation current oncardiac contraction. In fact, the main effect of the defibrillationcurrent is to reset the synchronization of the heart by forcing asignificant percentage of the cardiac tissue into a refractory state.Also, defibrillation currents are several orders of magnitude strongerthan pacing currents. It is a particular aspect of some embodiments ofthe present invention that the regular activation of the heart is notdisrupted, rather, the activation of the heart is controlled, over asubstantial number of cycles, by varying parameters of the reactivity ofsegments of cardiac muscle cells.

In some aspects of the invention, where the heart is artificially pacedin addition to being controlled in accordance with the presentinvention, the activation cycle of the heart is normal with respect tothe pacing. For example, when the control is applied locally, such thatthe activation of the rest of the heart is not affected.

In some aspect of the invention, the control is initiated as a responseto an unusual cardiac event, such as the onset of fibrillation or theonset of various types of arrhythmias. However, in other acts of thepresent invention, the control is initiated in response to a desiredincrease in cardiac output or other long-term effects, such as reducingthe probability of ventricular fibrillation (VF) or increasing thecoronary blood flow.

Another difference between defibrillation, pacing and some embodimentsof the present invention is that defibrillation and pacing are appliedas techniques to affect the entire heart (or at least an entirechamber), while certain embodiments of the present invention, forexample, fences (described below), are applied to local portion of theheart (which may be as large as an entire chamber) with the aim ofaffecting only local activity. Yet another difference between someembodiment of the present invention and defibrillation is in the energyapplied to the heart muscle. In defibrillation, a typical electric fieldstrength is 0.5 Joule (which is believed to be strong enough to exciterefractory tissue, “Optical Recordings . . . ”, cited above), while invarious embodiment of the invention, the applied field strength isbetween 50 and 500 micro joules, a field strength which is believed tonot cause action potentials in refractory tissue.

It is a further object of some aspects of the present invention toprovide a complete control system for the heart which includes, interaria, controlling the pacing rate, refractory period, conductionvelocity and mechanical force of the heart. Except for heart rate, eachof these parameters may be locally controlled, i.e., each parameter willbe controlled in only a segment of cardiac muscle. It should be notedthat heart rate may also be locally controlled, especially with the useof fences which isolate various heart segments from one another,however, in most cases this is detrimental to the heart's pumpingefficiency.

In one preferred embodiment of the present invention, electrical and/ormechanical activity of a segment of cardiac muscle is controlled byapplying a non-exciting field (voltage) or current across the segment. Anon-exciting signal may cause an existing action potential to change,but it will not cause a propagating action potential, such as thoseinduced by pacemakers. The changes in the action potential may includeextension of the plateau duration, extension of the refractory period,shortening of the post-plateau repolarization and other changes in themorphology of the action potential. However, the non-exciting signal mayaffect a later action potential, for example, it may delay such apotential or may accelerate its onset. Another type of non-excitingsignal is a voltage which does not cause a new contraction of thecardiac muscle cell to which the non-exciting signal is applied.Activation potential generation may be averted either by applyingvoltage of the wrong polarity; the voltage being applied when the celland/or the surrounding cells are not sensitive to it or by the amplitudeof the voltage being too small to depolarize the cell to the extent thata new action potential will be generated during that period.

Optionally, this control is exerted in combination with a pacemakerwhich applies an exciting signal to the heart. In a preferred embodimentof the invention, a pacemaker (or a defibrillator) incorporates acontroller, operating in accordance with at least one embodiment of theinvention. A pacemaker and a controller may share a battery, amicro-controller, sensors and possibly electrodes.

In another preferred embodiment of the present invention, arrhythmiasand fibrillation are treated using fences. Fences are segments ofcardiac muscle which are temporarily inactivated using electricalfields. In one example, atrial fibrillation is treated by channeling theactivation signal from an SA node to an AV node by fencing it in. Inanother example, fibrillations are damped by fencing in the multitude ofincorrect activation signals, so that only one path of activation isconducting. In still another example, ventricular tachycardia orfibrillation is treated by dividing the heart into insulated segments,using electrical fields and deactivating the fences in sequence with anormal activation sequence of the heart, so that at most only onesegment of the heart will be prematurely activated.

In still another preferred embodiment of the invention, the muscle massof the heart is redistributed using electrical fields. In general,changing the workload on a segment of cardiac muscle activatesadaptation mechanisms which tend to change the muscle mass of thesegment with time. Changing the workload may be achieved, in accordancewith a preferred embodiment of the invention, by increasing ordecreasing the action potential plateau duration of the segment, usingapplied electrical fields. Alternatively or additionally, the workloadmay be changed indirectly, in accordance with a preferred embodiment ofthe invention, by changing the activation time of the segment of theheart and/or its activation sequence. Further additionally ofalternatively, the workload may be changed by directly controlling thecontractility of a segment of the heart.

In yet another preferred embodiment of the invention, the operation ofthe cardiac pump is optimized by changing the activation sequence of theheart and/or by changing plateau duration at segments of the heartand/or by changing the contractility thereat.

In still another preferred embodiment of the invention, the cardiacoutput is modified, preferably increased, by applying a non-excitatoryelectric field to a segment of the heart, preferably the left ventricle.Preferably, the extent of increase in cardiac output, especially theleft ventricular output, is controlled by varying the size of thesegment of the heart to which such a field is applied. Alternatively oradditionally, the strength of the electric field is changed.Alternatively or additionally, the timing of the pulse is changed.Alternatively or additionally, the duration, shape or frequency of thepulse is changed. The increase in output may include an increase in peakflow rate, in flow volume, in average flow rate, or it may include achange in the flow profile, such as a shift in the development of thepeak flow, which improves overall availability of blood to body organs.

In still another preferred embodiment of the invention, the developedventricular pressure is modified, preferably increased, by applying anon-excitatory electric field to a segment of the heart, preferably theleft ventricle. Preferably, the extent of increase in cardiac output iscontrolled by varying the size of the segment of the heart to which sucha field is applied. Alternatively or additionally, the strength of theelectric field is changed. Alternatively or additionally, the timing ofthe pulse is changed. Alternatively or additionally, the duration of thepulse is changed. Alternatively or additionally, the waveform of thepulse is changed. Alternatively or additionally, the frequency of thepulse is changed. The increase in pressure may include an increase inpeak pressure, average pressure or it may include a change in thepressure profile, such as a shift in the development of the peakpressure, which improves the contractility.

In accordance with yet another preferred embodiment of the invention,the afterload of the heart is increased by applying non-excitatoryelectric fields to at least a segment of the heart, whereby the flow inthe coronary arteries is improved.

In accordance with another preferred embodiment of the invention variouscardiac parameters are controlled via inherent cardiac feedbackmechanisms. In one example, the heart rate is controlled by applying anon-exciting voltage to pacemaker cells of the heart, at or near the SAnode of the heart. Preferably, the heart rate is increased by applyingthe non-excitatory field.

In a preferred embodiment of the invention, a single field is applied toa large segment of the heart. Preferably, the field is applied at a timedelay after the beginning of the systole. Preferably, the non-excitingfield is stopped before half of the systole is over, to reduce thechances of fibrillation.

In another preferred embodiment of the invention, a plurality ofsegments of the heart are controlled, each with a differentnon-excitatory electric field. Preferably, each electric field issynchronized to the local activation or other local parameters, such asinitiation of contraction. A further preferred embodiment of theinvention takes into account the structure of the heart. The heartmuscle is usually disposed in layers, with each layer having a(different) muscle fiber orientation. In this embodiment of theinvention, a different field orientation and/or polarity is preferablyapplied for different orientations of muscle fibers.

In one preferred embodiment of the invention, this technique, whichtakes the muscle fiber orientation into account, may be applied to localdefibrillation-causing electric fields, the purpose of which fields maybe to delay the repolarization of a certain, limited segment of theheart, thereby creating a fence.

There is therefore provided in accordance with a preferred embodiment ofthe invention, a method of modifying the force of contraction of atleast a portion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, which causes the force ofcontraction to be increased by at least 5%.

Preferably, the force is increased by a greater percentage such as atleast 10%, 30% or 50%.

There is ither provided, in accordace with a preferred embodient of theinvention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a hearts comprising at least a portion havingan activation, and

applying a non-excitatory electric field having a given duration, to theportion at a delay of less than 70 msec after the activation.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying the force of contraction of at leasta portion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, which causes the in thechamber to be increased by at least 2%.

Preferably the pressure is increased by a greater amount such as atleast 10% or 20%.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying the force of contraction of at leasta portion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, wherein the chamber has aflow volume and wherein the flow volume is increased by at least 5%.

Preferably, the flow volume is increased by a greater amount such as atleast 10% or 20%.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying the force of contraction of at leasta portion of a heart chamber. comprising:

providing a subject having a hearts comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, wherein the chamber has aflow rate such that the flow rate is increased by at least 5%.

Preferably, the flow rate is increased by a greater amount such as atleast 10% or 20%.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying the force of contraction of at leasta portion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field to the portion at a delay afterthe activation, the field having a given diction of at least 101 msecand not lasting longer than the cycle length. Preferably the duration islonger, such as at least 120 msec or 150 msec.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the portion of the chamber has an inner surface and an outersurface and wherein the field is applied between the inner surface andthe outer surface.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the portion of the chamber has an inner surface and an outersurface and wherein the field is applied along the outer surface.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the portion of the chamber has an inside surface, an outsidesurface and an intra-muscle portion and wherein the field is appliedbetween the intra-muscle portion and at least one of the surfaces.

There is further provided, in accordance with a preferred embedment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the field is applied between a single electrode and a casing ofan implanted device.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contortion of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, using an electrode floatinginside the heart.

There is further provided in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the field is applied using at least two electrodes and whereinthe at least two electrodes are at least 2 cm apart.

In preferred embodiments of the invention the electrodes are at least 4or 9 cm apart.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the field is applied using at least two electrodes and whereinone electrode of the at least two electrodes is at a base of a chamberof the heart and one electrode is at an apex of a chamber of the heart.

There is her provided, in accordance with a preferred embodiment of theinvention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation, and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the field is applied using at least three electrodes and whereinapplying a non-excitatory field comprises:

electrifying a first pair of the at least three electrodes; and

subsequently electrifying a second pair of the at least threeelectrodes.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, wherein the field is appliedusing at least two electrodes placed externally to the subject.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion,

wherein the electric field at least partially cancels electroniccurrents in at least the portion of the heart chamber.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion between two positions; and

sensing an activation at a site between the two positions.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion between two positions; and

sensing an activation at a site coinciding with one of the twopositions.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

applying a non-excitatory electric field having a given duration, at adelay after the to activation, to the portion between two positions;

sensing an activation at a site; and

estimating the activation of the portion from the sensed activation.

Preferably sensing comprises sensing a value of a parameter of an ECGand wherein estimating comprises estimating the delay based on a delayvalue associated with the value of the parameter.

Preferably, the site is at a different chamber of the heart than thechamber at which the field is applied.

Preferably, the site is substantially the earliest activated site in thechamber of the portion.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion; and

applying a second non-excitatory electric field to a second portion ofthe chamber.

The is further provided, in accordance with a preferred embodiment ofthe invention a method according to claim 36, wherein the second fieldis applied in the same cardiac cycle as the non-excitatory field.

Preferably, each portion has an individual activation to which theapplications of the field threat are synchronized.

Preferably, the second field has a different effect on the heart thanthe non-excitatory field.

Preferably, only the second non-excitatory field is applied during adifferent cardiac cycle.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

estimating the activation at the portion; and

applying a non-excitatory electric field having a given duration, at adelay after the estimated activation, to the portion.

There is ether provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising;

providing a subject having a heart, comprising at least a portion havingan activation;

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion; and

repeating application of the non-excitatory field, during a plurality oflater heart beats, at least some of which are not consecutive.

Preferably, the method comprises gradually reducing the frequency atwhich beats are skipped during the repeated application.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

applying a non-excitatory electric field having a given duration, at adelay after the activation, to the portion, wherein the portion has anextent; and

changing the extent of the portion to which the field is applied,between beats.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

irradiating the portion with light synched to the activation; and

repeating irradiating at least 100 cardiac cycles, during a period ofless than 1000 cardiac cycles.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation;

irradiating the portion with radio frequency radiation synched to theactivation; and

repeating irradiating at least 100 cardiac cycles, during a period ofless than 1000 cardiac cycles.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

modifying the availability of calcium ions inside muscle fibers of theportion, during a period of time including a time less than 70 msecafter the activation, in response to the activation.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

modifying the transport rate of calcium ions inside muscle fibers of theportion, during a period of time less than 70 msec after the activation,in response to the activation.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying a force of contraction of at least aportion of a heart chamber, comprising:

providing a subject having a heart, comprising at least a portion havingan activation; and

modifying the availability of catecholamines at the portion in synchronywith the activation.

There is further provided in accordance with a preferred embodiment ofthe invention a method of modifying the activation profile of at least aportion of a heart, comprising,

mapping the activation profile of the portion;

determining a desired change in the activation profile; and

modifying, using a non-excitatory electric field, the conductionvelocity in a non-arrhythmic segment of the portion, to achieve thedesired change.

In a preferred embodiment of the invention, wherein the desired changeis an AV interval and wherein modifying comprises modifying theconduction velocities of purkinje fibers between an AV node and at leastone of the ventricles in the heart.

In a preferred embodiment of the invention, the activation comprises anaverage activation of the portion.

In a preferred embodiment of the invention, the activation comprises anearliest activation.

In a preferred embodiment of the invention, the activation comprises amechanical activation.

In a preferred embodiment of the invention, wherein the activationcomprises an electrical activation.

In a preferred embodiment of the invention, wherein the portioncomprises a plurality of subportions, each having an individualactivation and wherein applying a field comprises applying a field toeach subportion at a delay relative to the individual activation of thesubportion.

In a preferred embodiment of the invention, applying a non-excitatoryelectric field comprises driving an electric current through thesegment. Preferably, the current is less than 20 mA. In some embodimentsof the invention the current is less than 8 mA, 5 mA, 3 mA. Preferably,the current is at least 0.5 mA. In some embodiments it is at least 1 or3 mA.

In a preferred embodiment of the invention, the field is applied for aduration of between 10 and 140 msec. In other preferred embodiments itis applied for between 20 and 100 msec, or 60 and 90 msec.

In a preferred embodiment of the invention, the delay is less than 70msec. In other preferred embodiments it is less than 40, 20, 5 or 1msec. In some embodiments the delay is substantially equal to zero.

In a preferred embodiment of the invention, the delay is at least 1msec. In other preferred embodiments it may be more than 3, 7, 15 or 30msec.

In a preferred embodiment of the invention, the electric field has anexponential temporal envelope. In others it has a square, triangular,ramped or biphasic temporal envelope. Preferably the electric fieldcomprises an AC electric field, preferably having a sinusoidal, sawtooth or square wave temporal envelope.

In a preferred embodiment of the invention, wherein the portion of thechamber has an inside surface and an outside surface, wherein the fieldis applied along the inner surface.

In a preferred embodiment of the invention, wherein the portion of thechamber has a normal conduction direction, wherein the field is appliedalong the normal conduction direction.

In a preferred embodiment of the invention, wherein the portion of thechamber has a normal conduction direction, wherein the field is appliedperpendicular to the normal conduction direction.

In a preferred embodiment of the invention, the field is applied betweenat least two electrodes. Preferably, the electrodes are at least 2 cmapart. In some preferred embodiments the electrodes are at least 4 or 9an apart.

The chamber may be any of the left ventricle, the left atrium, the rightventricle or the right atrium.

A preferred embodiment of the invention includes pacing the heart.Preferably, applying the electric field is synchronized with the pacing.

In a preferred embodiment of the invention, the method includescalculating the delay based on the pacing.

In a preferred embodiment of the invention, the method includes sensinga specific activation at a site.

There is further provided, in accordance with a preferred embodiment ofthe invention, a method of modifying the activation profile of at leasta portion of a heart, comprising,

mapping the activation profile of the portion;

determining a desired change in the activation profile; and

blocking the activation of at least a segment of the portion, to achievethe desired change, wherein the segment is not part of a reentry circuitor an arthythmia foci in the heart.

In a preferred embodiment of the invention, the blocked segment is anischemic segment.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying the activation profile of at least aportion of a heart, comprising,

mapping the activation profile of the portion;

determining a desired change in the activation profile; and

changing the refractory period of at least a segment of the portion, toachieve the desired change, wherein the segment is not part of a reentrycircuit or an arthythmia foci in the heart.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying the heart rate of a heart,comprising:

providing a subject having a heart with an active natural pacemakerregion; and

applying a non-excitatory electric field to the region.

Preferably, the electric field extends a duration of an action potentialof the region.

Preferably the method comprises extending the refractory period of asignificant portion of the right atrium.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of reducing an output of a chamber of a heart,comprising:

determining the earliest activation of at least a portion of thechamber, which portion is not part of an abnormal conduction pathway inthe heart; and

applying a non-excitatory electric field to the portion.

Preferably, the field is applied prior to activation of the portion.

Preferably, the field reduces the reactivity of the portion to anactivation signal.

Preferably, the field reduces the sensitivity of the portion to anactivation signal.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of reducing an output of a chamber of a heart,comprising:

determining an activation of ad conduction pathways to at least aportion of the chamber; and

reversibly blocking the conduction pathways, using a locally appliednon-excitatory electric field.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of reducing an output of a chamber of a heart,comprising:

determining an activation of and a conduction pathway to at least aportion of the chamber, which portion is not part of an abnormalconduction pathway in the heart; and

reversibly reducing the conduction velocity in the conduction pathway,using a locally applied electric field.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of performing cardiac surgery, comprising:

blocking the electrical activity to at least a portion of the heartusing a non-excitatory electric field; and

performing a surgical procedure on the portion.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of performing cardiac surgery, comprising:

reducing the sensitivity to an activation signal of at least a portionof the heart using a non-excitatory electric field; and

performing a surgical procedure on the portion.

There is further provide in accordance with a preferred embodiment ofthe invention a method of controlling the heart, comprising,

providing a subject having a heart with a left ventricle and a rightventricle;

selectively reversibly increasing the contractility of one of theventricles relative to the other ventricle.

Preferably, selectively reversibly increasing comprises applying anon-excitatory electric field to at least a portion of the oneventricle.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of controlling the heart, comprising,

providing a subject having a heart with a left ventricle and a rightventricle;

selectively reversibly reducing the contractility of one of theventricles, relative to the other ventricle.

Preferably, selectively reversibly reducing comprises applying anon-excitatory electric field to at least a portion of the oneventricle.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of treating a segment of a heart which is inducesarrhythmias due to an abnormally low excitation threshold, comprising:

identifying the segment; and

applying a desensitizing electric field to the segment, such that theexcitation threshold is increased to a normal range of values.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of modifying an activation profile of at least aportion of a heart, comprising:

determining a desired change in the activation profile; and

reversibly blocking the conduction of activation signals across aplurality of elongated fence portions of the heart to achieve thedesired change.

Preferably, blocking the conduction creates a plurality of segments,isolated from external activation, in the portion of the heart.Preferably, at least one of the isolated segments contains an arthythmiafoci. Preferably, at least one of the isolated segments does not containan arthythmia foci.

Preferably, the method includes individually pacing each of at least twoof the plurality of isolated segments.

Preferably, blocking the conduction limits an activation front fromtraveling along abnormal pathways.

Preferably, reversibly blocking comprises reversibly blocking conductionof activation signals, synchronized with a cardiac cycle, to blockabnormal activation signals.

In a preferred embodiment of the invention reversibly blocking comprisesreversibly blocking conduction of activation signals, synchronized witha cardiac cycle, to pass normal activation signals.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of treating abnormal activation of the heart,comprising:

detecting an abnormal activation state; and

modifying the activation of the heart in accordance with the abovedescribed method to stop tie abnormal activation condition.

In a preferred embodiment of the invention the abnormal condition isfibrillation.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of controlling the heart comprising:

determining a desired range of values for at least one parameter ofcardiac activity; and

controlling at least a local force of contraction in the heart tomaintain the parameter within the desired range.

Preferably, controlling includes controlling the heart rate.

Preferably, controlling includes controlling a local conductionvelocity.

Preferably, the parameter responds to the control with a time constantof less than 10 minutes. Alternatively it responds with a time constantof more an a day.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of controlling the heart, comprising:

determining a desired range of values for at least one parameter ofcardiac activity;

controlling at least a portion of the heart using a non-excitatoryelectric field having at least one characteristic, to maintain theparameter within the desired range; and

changing the at least one characteristic in response to a reduction in areaction of the heart to the electric field.

Preferably, the characteristic is a strength of the electric field.Alternatively it comprises a duration of the electric field, a frequencyof the field or a wave form of the field.

There is further provided in accordance with a preferred embodiment ofthe invention method of treating a patient having a heart with anunhealed infarct, comprising, applying any of the above methods, untilthe infarct is healed.

There is further provided, in accordance with a preferred embodiment ofthe invention method of treating a patient having a heart, comprising,

providing a patient, having an unhealed infarct in the heart; and

applying one of the above methods until the heart is stabilized,

In a preferred embodiment of the invention applying a non-excitatoryfield comprises applying a non-excitatory field for between 3 and 5000heart beats.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration at least 100 times during a periodof less than 50,000 cardiac cycles.

Preferably, are electrified at least 1000 times during a period of lessthan 50,000 cardiac cycles. They may also be electrified at least 1000times during a period of less than 20,000 cardiac cycles or at least1000 times during a period of less than 5,000 cardiac cycles.

Preferably, the field is applied less than 10 times in one second.

In a preferred embodiment of the invention, the power supply electrifiesthe electrodes at least 2000 times over the period. In preferredembodiments the power supply electrifies the electrodes at least 4000times over the period.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration,

wherein at least one of the electrodes is adapted to cover an area ofthe heart larger than 2 cm².

Preferably at least one of the electrodes is adapted to cover an area ofthe heart larger than 6 or 9 cm².

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

at least one unipolar electrode adapted to apply an electric field to atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field.

Preferably the apparatus comprises a housing, which is electrified as asecond electrode.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration,

wherein the distance between the electrodes is at least 2 cm.

In preferred embodiments of the invention the distance is at least 4 or9 cm.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

at least three electrodes adapted to apply an electric field across atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration,

wherein the electrodes are selectively electrifiable in at least a firstconfiguration where two electrodes are electrified and in a secondconfiguration where two electrodes, not both identical with the firstconfiguration electrodes, are electrified.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart;

a sensor which senses a local activation; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a give duration, responsive to the sensed localactivation.

Preferably the sensor senses a mechanical activity of the portion.

Preferably, the sensor is adapted to sense the activation at least oneof the electrodes.

Preferably, the sensor is adapted to sense the activation in the rightatrium.

Preferably, the sensor is adapted to sense the activation between theelectrodes.

Preferably, the sensor senses an earliest activation in a chamber of theheart including the portion and wherein the power supply times theelectrification responsive to the earliest activation.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

electrodes adapted to apply an electric field across elongate segmentsof at least a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field.

Preferably, the electrodes are elongate electrodes at least one cm long.In other embodiments they are at least 2 or 4 cm long. Preferably thesegments are less than 0.3 cm wide. In some embodiments they are lessthan 0.5, 1 or 2 cm wide.

Preferably, the power supply electrifies the electrodes for a givenduration of at least 20 msec, at least 1000 times over a period of lessthan 5000 cardiac cycles.

In preferred embodiments of the invention, the elongate segments dividethe heart into at least two electrically isolated segments in the heart.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart;

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration; and

a circuit for determining an activation at a site in the portion,

wherein the power supply electrifies the electrodes responsive to thedetermined activation.

Preferably, the electric field is applied at a given delay, preferablyless than 70 msec, after an activation at one of the electrodes.

In a preferred embodiment of the invention the electric field is appliedbefore an activation at one of the electrodes. In various preferredembodiments of the invention the field is applied more than 30, 50 or 80msec before the activation.

Preferably, the circuit comprises an activation sensor which senses theactivation. Alternatively or additionally the activation is calculated,preferably based on an activation in a chamber of the heart differentfrom a chamber including the portion.

Preferably the apparatus includes a memory which stores values used tocalculate a delay time, associated with a value of at least a parameterof a sensed ECG. Preferably, the parameter is a heart rate.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart;

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration;

a sensor which measures a parameter of cardiac activity; and

a controller which controls the electrification of the electrodes tomaintain the parameter within a range of values.

The apparatus preferably comprises a memory which stores a map ofelectrical activity in the heart, wherein the controller uses the map todetermine a desired electrification.

The apparatus preferably comprises a memory which stores a model ofelectrical activity in the heart, wherein the controller uses the modelto determine a desired electrification.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart;

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration; and

a controller which measures a reaction of the heart to theelectrification of the electrodes.

Preferably, the controller changes the electrification based on themeasured reaction. Preferably, the apparatus includes a memory whichstores the measured reaction.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart;

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration; and

a pacemaker which paces the heart.

Preferably, the pacemaker and the remainder of the apparatus arecontained in a common housing.

Preferably, the pacemaker and the remainder of the apparatus utilizecommon excitation electrodes. Preferably, the pacemaker and theremainder of the apparatus utilize a common power supply.

Preferably, the non-excitatory field is synchronized to the pacemaker.

Preferably, the electrodes are electrified using a single pulse whichcombines a pacing electric field and a non-excitatory electric field.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration,

wherein at least one of the electrodes is mounted on a catheter.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for controlling a heart comprising:

a plurality of electrodes adapted to apply an electric field across atleast a portion of the heart; and

a power supply which electrifies the electrodes with a non-excitatoryelectric field, for a given duration,

wherein the electrodes are adapted to be applied externally to the body.

Preferably, the apparatus includes an external pacemaker.

Preferably, the apparatus comprises an ECG sensor, to whichelectrification of the electrodes is synchronized.

In a preferred embodiment of the invention the duration of the field isat least 20 msec.

In other preferred embodiments the duration is at least 40, 80 or 120.

In a preferred embodiment of the invention a current is forced throughthe portion, between the electrodes.

Preferably, the apparatus includes at least another two electrodes,electrified by the power supply and adapted to apply a non-excitatoryelectric field across a second portion of the heart. Preferably, theapparatus comprises a controller which coordinates the electrificationof all the electrodes in the apparatus.

Preferably, a peak current through the electrodes is less than 20 mA. Insome preferred embodiments it is less than 10, 5 or 2 mA.

In preferred embodiments of the invention the electrodes are adapted tobe substantially in contact with the heart.

Preferably the electric field has an exponential, triangular or squarewave shape. The field may be unipolar or bipolar. The field may have aconstant strength.

There is further provided, in accordance with a preferred embodiment ofthe invention apparatus for optical control of a heart, comprising:

at least one implantable light source which generates pulses of light,for at least 1000 cardiac cycles, over a period of less than 3000cycles; and

at least one wave guide for providing non-damaging intensities of lightfrom the light source to at least one site on the heart.

Preferably, the at least one light source comprises a plurality of lightsources, each attached to a different site on the heart.

Preferably, the wave guide is an optical fiber.

Preferably, the light source comprises a monochrome light source.

In a preferred embodiment of the invention the apparatus comprises asensor, which measures an activation of at least portion of the heart,wherein the light source provides pulsed light in synchrony with themeasured activation.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of programming a programmable controller for asubject having a heart, comprising:

determining pulse parameters suitable for controlling the heart usingnon-excitatory electric fields; and

programming the controller with the pulse parameters.

Preferably, determining pulse parameters comprises determining a timingof the pulse relative to a cardiac activity.

Preferably, the cardiac activity is a local activation.

Preferably, determining a timing comprises determining timing which doesnot induce fibrillation in the heart.

Preferably, determining a timing comprises determining a timing whichdoes not induce an arthythmia in the heart.

Preferably, determining a timing comprises determining the timing basedon a map of an activation profile of the heart.

Preferably, determining a timing comprises calculating a delay timerelative to a sensed activation.

Preferably, controlling the heart comprises modifying the contractilityof the heart.

There is further provided, in accordance with a preferred embodiment ofhe invention a method of determining an optimal placement of at leasttwo individual electrodes for controlling a heart using non-excitatoryelectric fields, comprising:

determining an activation profile of at least a portion of the heart;and

determining an optimal placement of the electrodes in the portion basedon the activation profile.

Preferably the method includes determining an optimal location for anactivation sensor, relative to the placement of the electrodes.

Preferably, controlling comprises modifying the contractility.

Preferably, controlling comprises creating elongate non-conductingsegments in the heart.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of determining a timing parameter for anon-excitatory, repeatably applied pulse for a heart, comprising:

applying a non-excitatory pulse using a first delay;

determining if the pulse induces an abnormal activation profile in theheart; and

repeating applying a non-excitatory pulse using a second delay, shorterthan the first, if the pulse did not induce abnormal activation in theheart.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of determining a timing parameter for anon-excitatory, repeatably applied pulse for a heart, comprising:

applying a non-excitatory pulse using a first delay;

determining if the pulse induces an abnormal activation profile in theheart; and

repeating applying a non-excitatory pulse using a second delay, longerthan the first, if the pulse did not induce abnormal activation in theheart.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of programming a programmable controller for aheart, comprising:

controlling the heart using plurality of non-excitatory electric fieldsequences;

determining a response of the heart to each of the sequences; and

programming the controller responsive to the response of the heart tothe non-excitatory sequences.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of controlling an epileptic seizure, comprising:

detecting an epileptic seizure in brain tissue; and

applying a non-excitatory electric field to the brain tissue toattenuate conduction of a signal in the tissue.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of controlling nervous signals in peripherynerves, comprising,

selecting a nerve; and

applying a non-excitatory electric field to the nerve to attenuateconduction of nervous signals in the nerve.

There is further provided, in accordance with a preferred embodiment ofthe invention a method of controlling a heart having a chambercomprising:

applying a non-excitatory electric field to a first portion of achamber, such that a force of contraction of the first portion islessened; and

applying a non-excitatory electric field to a second portion of achamber, such that a force of contraction of the second portion isincreased, heart beat. Alternatively or additionally, the delay is atleast 0.5 or 1 msec, optionally, 3 msec, optionally 7 msec and alsooptionally 30 msec.

There is further provided in accordance with a preferred embodiment ofthe invention, a method of controlling the heart including determining adesired range of values for at least one parameter of cardiac activityand controlling at least a local contractility and a local conductionvelocity in the heart to maintain the parameter within the desiredrange.

Preferably, the parameter responds to the control with a time constantof less than 10 minutes, alternatively, the parameter responds to thecontrol with a time constant of between 10 minutes and 6 hours,alternatively, with a time constant of between 6 hours and a day,alternatively, with a time constant between a day and a wealternatively, a time constant of between a week and month,alternatively, a time constant of over a month.

There is also provided in accordance with a preferred embodiment of theinvention, a method of controlling the heart, including determining adesired range of values for at least one parameter of cardiac activity,controlling at least a portion of the heart using a non-excitatoryelectric field having at least one characteristic, to maintain theparameter within the desired range and changing the at least onecharacteristic in response to a reduction in a reaction of the heart tothe electric field. Preferably, the characteristic is the strength ofthe electric field. Alternatively or additionally, the characteristic isone or more of the duration of the electric field, its timing, waveform, and frequency.

In another preferred embodiment of the invention, the apparatus includesa sensor which measures a parameter of cardiac activity and a controllerwhich controls the electrification of the electrodes to maintain theparameter within a range of values. Preferably, the apparatus includes amemory which stores a map of electrical activity in the heart, whereinthe controller uses the map to determine a desired electrification.Alternatively or additionally, the apparatus includes a memory whichstores a model of electrical activity in the heart, wherein thecontroller uses the model to determine a desired electrification.

There is also provided in accordance with a preferred embodiment of theinvention, a method of controlling an epileptic seizure, includingdetecting an epileptic seizure in brain tissue and applying anon-excitatory electric field to the brain tissue to attenuateconduction of a signal in the tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more clearly understood from the detaileddescription of the preferred embodiments and from the attached drawingsin which:

FIG. 1A is a schematic graph of a typical cardiac muscle actionpotential;

FIG. 1B is a schematic model of a cardiac muscle cell in an electricalfield;

FIG. 2 is a schematic diagram of a heart having segments controlled inaccordance with embodiments of the present invention;

FIG. 3 is a schematic diagram of a segment of right atrial tissue with aplurality of conduction pathways, illustrating the use of fences, inaccordance with a preferred embodiment of the present invention;

FIG. 4A is a schematic diagram of an electrical controller connected toa segment of cardiac muscle, in accordance with a preferred embodimentof the invention;

FIG. 4B is a schematic diagram of an electrical controller connected toa segment of cardiac muscle, in accordance with a preferred embodimentof the invention;

FIG. 5 is a schematic diagram of an experimental setup used for testingthe feasibility of some embodiments of the present invention;

FIGS. 6A-6C are graphs showing the results of various experiments;

FIG. 7A is a graph summarizing results of experimentation on an isolatedsegment of cardiac muscle fibers, and showing the effect of a delay inapplying a pulse in accordance with an embodiment of the invention, onthe increase in contractile force;

FIG. 7B is a graph summarizing results of experimentation on an isolatedsegment of cardiac muscle fibers, and showing the effect of a durationof the pulse on the increase in contractile force;

FIG. 7C is a graph summarizing results of experimentation on an isolatedsegment of cardiac muscle fibers, and showing the effect of a currentintensity of the pulse on the increase in contractile force;

FIG. 8A is a graph showing the effect of a controlling current on aheart rate, in accordance with a preferred embodiment of the invention;

FIG. 8B is a series of graphs showing the repeatability of increasingcontractility in various types of cardiac muscles, in accordance with apreferred embodiment of the invention;

FIGS. 9-18B are each a series of graphs showing experimental resultsfrom experiments in which an isolated rabbit heart was controlled inaccordance with an embodiment of the present invention; and

FIGS. 19-23 are each a series of graphs showing experimental resultsfrom experiments in which an in-vivo rabbit heart was controlled inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

One aspect of the preset invention relates to controlling and/ormodulating the contractility of a cardiac muscle segment and/or theplateau duration of an action potential of the cardiac muscle segment,by applying an electric field or current across the segment. As usedherein, the terms, voltage, electric field and current are usedinterchangeably to refer to the act of supplying a non-excitatory signalto control cardiac activity. The actual method of applying the signal isdescribed in more detail below.

FIG. 1B shows a schematic model illustrating one possible explanationfor the relation between an applied voltage and a resulting plateauduration. A cell 20, having a membrane 26, surrounded by extra-cellularfluid 28, is located in an electrical field generated by an electrode 22and an electrode 24. Cell 20 has a 40 mV internal potential acrossmembrane 26, electrode 22 has a potential of 40 mV and electrode 24 isgrounded (to the rest of the body). During the action potential plateau,calcium ions enter the cell and potassium ions leave the cell throughdifferent membrane proteins. In this model, the external electric fieldcaused by the voltage on the electrodes increases the potential ofextra-cellular fluid 28. This reduces the outward movement of potassiumions from inside cell 20 and/or forces calcium ions into cell 20, eitherby changing the membrane potential, thus changing the electrochemicaldriving force of ions from both sides of the membrane or by changing thenumber of ionic channels being opened or closed.

In an additional or alternative model, the electric field generated byelectrodes 22 and 24 causes an ionic flow between them. This flow iscarried mainly by chlorine and potassium ions, since these are the ionsto which membrane 26 is permeable, however, calcium ions may also beaffected. In this model, calcium ions are drawn into cell 20 by thecurrent while potassium ions are removed. Alternatively or additionally,sodium ions are removed instead of potassium ions. In any case, theadditional calcium ions in the cell increase the contractility of cell20 and are believed to extend the plateau duration.

Another additional or alternative model is that the electric fieldand/or the ionic current affect the opening and closing ofvoltages-gated channels (sodium, potassium and sodium-calcium). Further,the field may affect the operation of ionic pumps. One possiblemechanism for this effect is that the applied electric field generateslocal “hot spots” of high electrical fields in the cell membrane, whichhot spots can affect the opening and closing of ionic channels and/orpumps. Since creation of the hot spots is generally asymmetric withrespect to the cell and since the channels themselves have an asymmetricbehavior with respect to applied fields, more channels may be opened atone end of the cell than at the other. If, for example, more channelsopen at the negative end of the cell than at the positive end of thecell, the inflow of calcium ions will be greater than the outflow ofthese ions.

In accordance with yet another model, the controlling electric fieldincreases the concentration of calcium in intracellular stores, whichincreased concentration may cause increased and/or faster supply ofcalcium during contraction, increasing the contractile force.Alternatively or additionally, the controlling electric field maydirectly affect the rate at which calcium is made available from theintracellular store, during contraction of the cell. Also, it may bethat the controlling electric field directly increases the efficiency ofthe inflow of calcium, which causes an increase in the availability ofcalcium from the intracellular stores. It should be noted that in somephysiological models of myocyte contraction, it is the rate of calciumflow which determines the contractility, rather than the total amount ofcalcium.

Different types of ionic channels and pumps have different operatingcharacteristics. These characteristics include rates of flow, openingand closing rates, triggering voltage level, priming and dependency onother ions for operating. It is thus possible to select a particulartype of ionic channel by applying a particular strength of electricfield, which strength also depends on whether the channels are open orclosed at that moment, i.e., on the depolarization/repolarization phaseof the cell. Different attributes of cellular activity may be controlledby controlling the ionic channels in this manner, since the activity ofexcitable tissues are well determined by their transmembrane potentialand the concentrations of various types of ions inside and outside thecell.

Another model is that applying a non-excitatory electric fields inducesthe release of catecholamines (from nerve endings) at the treatedportion of the heart. Another possibility is that the applied fieldfacilitates the absorption of existing catecholamines by the cell.

Another, “recruitment”, model, hypothesizes that the non-excitatorypulse recruits cardiac muscle fibers which are otherwise not stimulatedby the activation signal. The non-excitatory pulse may work by loweringtheir depolarization threshold or by supplying a higher strengthactivation signal than is normal. However, it is generally accepted thatcardiac muscle fibers function as a syncytium such that each cellcontracts at each beat. See for example, “Excitation ContractionCoupling and Cardiac Contractile Force”, by Donald M. Bers, Chapter 2,page 17, Kluwer Academic, 1991.

Most probably, one or more of these models may be used to explain theactivity of cell 20 during different parts of the activation cycle.However, several major effects, including, increasing contractility,changing the self-activation rate, rescheduling of the repolarization,extension of plateau duration, hyperpolarization of cells, changing ofmembrane potential, changing of conduction velocity and inactivation ofcells using electric fields, can be effected without knowing whichmodel, if any, is correct.

As can be appreciated the direction of the electric field may beimportant. First, conduction in cardiac cells is very anisotropic.Second, the distribution of local irregularities in the cell membrane isnot equal, rather, irregularities are more common at ends of the cell;in addition, one cell end is usually more irregular than the other cellend. These irregularities may govern the creation of local high electricfields which might affect ionic channels. Third, some cardiacstructures, such as papillary muscles, are better adapted to conduct anactivation signal in one direction than in an opposite direction.Fourth, there exist rhythmic depolarization signals originating in thenatural conductive system of the heart which are caused by thedepolarization and repolarization of the heart muscle tissue itself.These signals may interfere with an externally applied electric field.

In one preferred embodiment of the invention, the purpose of aparticular electric field is to induce an ionic current which isopposite to an ionic current induced by the voltage potential caused bythe rhythmic depolarization of the heart. For example, the actionpotential plateau duration in cardiac muscle cells further from theearliest activation locations is typically shorter than the duration ofthose cells nearer the earliest activation location. This shortening mayresult from different local ionic currents caused by the depolarizationand repolarization of the heart and/or by different ionic currentkinetics behavior at these locations. These ionic currents can benegated by applying an electric field of an equal magnitude and oppositedirection to the field generated by the rhythmic depolarization.

FIG. 2 shows a heart 30 which is controlled using an electricalcontroller 32. A segment 38 of the right atrium is a controlled segment.In one preferred embodiment of the invention, the casing of controller32 is one electrode and an electrode 36 is a second electrode forapplying an electric field to segment 38. In another preferredembodiment of the invention, a second electrode 34 is used instead ofthe casing of controller 32. In a further preferred embodiment of theinvention, the body of controller 32 is a ground, so that both electrode34 and electrode 36 can be positive or negative relative to the rest ofthe heart. In another embodiment, electrode 34 is not directly connectedto heart 30, rather, electrode 34 is floating inside the hot. In thisembodiment, electrode 34 is preferably the current drain electrode. Forillustrative purposes, controller 32 is shown including a power supply31, leads 29A and 29B connecting the controller to the electrodes and amicroprocessor 33 which controls the electrification of the electrodes.

In an alternative embodiment, also shown in FIG. 2, the electric fieldis applied along the heart wall, rather than across it. A segment 35 ofthe left ventricle is shown to be controlled by two electrodes 37operated by a controller 39. Electrodes 37 may be placed on the surfaceof heart 30, alternatively, electrodes 37 may be inserted into the heartmuscle. Further alternatively, the electrodes may be placed in bloodvessels or in other body tissues which are outside of the heart,providing that electrifying the electrodes will provide a field orcurrent to at least a portion of the heart. It should be noted that,since the control is synchronized to the cardiac cycle, even if theelectrodes are outside the heart, there is substantially no change inposition of the heart between sequential heart beats, so substantiallythe same portion of the heart will be affected each cardiac cycle, evenif the electrodes are not mechanically coupled to the heart.

It another alternative embodiment of the invention, more than one pairof electrodes is used to control segment 35. In such an embodiment, eachpair of electrodes may be located differently with respect to segment35, for example, one pair of electrodes may be placed on the epicardiumand a second pair placed inside the myocardium.

It should be appreciated that a current induced between the electrodesmay cause electrolytic deposition on the electrodes over a period oftime and/or may cause adverse physiological reactions in the tissue. Tocounteract this effect, in a preferred embodiment of the invention, theelectric field is an AC electric field. In one preferred embodiment, thedirection of the field is switched at a relatively low frequency, equalto or lower than the cardiac cycle rate. Preferably, the phase isinverted during a particular phase of the cardiac cycle, for example,during diastole. In another preferred embodiment of the invention, theelectric field has a frequency which is significantly higher than thecardiac cycle frequency.

Fast sodium channels, once inactivated require a certain amount of timeat a negative potential to become ready for activation. As describe forexample, in “Ionic Channels of Excitable Membranes”, Bertil Hille,chapter 2, pp. 40-45, Sinaur Associates Inc., the disclosure of which isincorporated herein by reference. Since most sodium channels are notactivated immediately at the onset of depolarization, applying a voltageat a high enough frequency can open the few channels that do reactquickly to potential changes, while most of the channels will becomeinactivated and will not leave the inactivation stage. Thus, if thefrequency of the field is high enough, certain ionic channels can bekept closed even though the average voltage is zero, within the resultthe stimulated tissue is non-excitatory.

In accordance with another preferred embodiment of the invention an ACfield is overlaid an a DC field for controlling the heart. For example,an AC field having a amplitude of 20% that of the DC field and afrequency of 1 kHz may be used. Such an AC/DC controlling field has theadvantage that the change in the applied field is higher, so that anyreactions (on the part of the muscle cell) to changes in the field arefacilitated, as are any reactions to the intensity of the field. The ACfield in a combined AC/DC field or in a part AC type field may have atemporary form of a sawtooth, a sinusoid or another form, such as anexponential or square wave pulse form.

In a DC type field, the temporal form of the field is preferably that ofa constant amplitude pulse. However, in other embodiment of theinvention a triangular pulse, an exponential pulse, a ramp shaped pulse(increasing or decreasing), and/or a biphasic pulse form may be used.

Both AC and DC fields may be unipolar or bipolar. The terms AC and DC,as used herein to describe the electric field, relate to the number ofcycles in a pulse. A DC filed has at most one cycle, while an AC fieldmay comprise many cycles. In other preferred embodiments of theinvention, a train of pulses may be applied, each train being of an ACor of a DC type.

Various types of ionic electrodes, such as Ag—AgCl electrodes, platinumelectrodes, titanium electrodes with coatings such as nitrides andcarbides, coated tantalum electrodes, pyrocarbon electrodes or carbonelectrodes maybe used. These electrodes generally reduce the amount ofelectro-deposition. The electrodes may be square, rectangular or of anyother suitable shape and may be attached by screwing the electrode intothe myocardium or by clamping or by other attachment methods.

There are two preferred methods of delivering an electric field to asegment of the heart. In a first method, a current is forced through thesegment of the heart which is to be controlled. Preferably, the currentis a constant DC current. However, an AC current, as described above mayalso be used. In a second method, an electric field is applied acrossthe heart (and maintained at a constant strength relative to the signalfrom). Generally, applying an electric field is easier and requires lesspower than inducing a current.

The timing of the application of the electric field (or current)relative to the local activity at segment 38 and relative to the entirecardiac cycle is important. In general, the application of the field maybe synchronized to the local activation time if a local effect isdesired, such as increasing the local contractility and/or plateauduration. The application of the field may be synchronized to thecardiac cycle in cases where a global effect is desired. For example, byhyperpolarizing cells in synchrony with the cardiac cycle it is possibleto time their excitability window such that certain arrhythmias areprevented, as described in greater detail below. The application of thefield may also be synchronized in accordance with a model of how theheart should be activated, in order to change the activation profile ofthe heart. For example, to increase the output of the heart, conductionvelocities and/or conduction pathways may be controlled so that theheart contracts in a sequence deemed to be more optimal than a naturalsequence. In particular, by controlling the conduction velocity at theAV node and/or at the left and right branches the AV interval may beincreased or reduced. It should however be appreciated that thedifference in activation times between different parts of the heart,especially in the same chamber of the heart, is usually quite small. Forexample, the propagation time of an activation signal in the leftventricle is approximately between 15 and 50 msec. If the controlfunction may be achieved even if the timing of the application of thecontrolling field is locally off by 5 or 10 msec, then the controlfunction can be achieved using a single pair of controlling electrodes.

Although it is usually simplest to determine the local activation usinga measured electrical activation time, it should be appreciated that thelocal activation of a tissue segment may be determined based on changesin mechanical activity, changes in position, velocity of motion,acceleration and even transmembrane potentials. Further, since indiseased tissue the delay between electrical activation and mechanicalactivation may be longer than in healthy tissue, the timing of theapplication of the field is preferably relative to the mechanicalactivation of the muscle.

In a preferred embodiment of the invention, the timing of the field isrelative to the actual transmembrane potentials in the segments, notthose which may be estimated from the electrogram and/or the mechanical.Thus, initiation of the field may be timed to the onset of the plateauto increase contractility. Alternatively, application of the field maybe timed to specific transmembrane voltage levels. Further preferably,the strength and/or other parameters of the field, may be determinedresponsive to the actual transmembrane potentials and ionicconcentrations achieved in cells of the segment. One way of determiningthe actual voltage levels is to inject a voltage sensitive dye into thecell and monitor it using an optical sensor, such as known in the art inexperimental settings. One way of monitoring ionic concentrations, bothintracellular and extracellular is by using concentration sensitivedyes.

If an electric field is applied before the activation signal reachessegment 38, the electric field can be used to reduce the sensitivity ofsegment 38 to the activation signal. One method of producing this effectis to apply a large electric field opposite to the direction of theactivation signal and synchronized to it. This field will reduce theamplitude of the activation signal, so that it cannot excite cardiactissue. Another method is to apply a strong positive potential onsegment 38 before an activation signal reaches it, so that segment 38 ishyperpolarized and not sensitive to the activation signal. Removing theelectric field does not immediately reverse this effect. Segment 38stays insensitive for a short period of time and for a further period oftime, the conduction velocity in segment 38 is reduced. In some caseshowever, removing the electric field will cause an action potential tooccur. This action potential can be timed so that it occurs during asafe period with respect to the activation profile of the heart, so thatif the segment generates an activation signal, this signal will not bepropagated to other parts of the heart in some cases, the application ofthe field may affect the reactivity of the cells to the electricalpotential rather and, in others, it may extend the refractory period. Itshould be noted that an electric field applied shortly after activationmay also extend the refractory period, in addition to increasing theforce of contraction.

It should be noted that, since the cardiac cycle is substantiallyreported, a delay before the activation time and a delay after theactivation time may both be embodied using a system which delays afterthe activation time. For example, a field which should be applied 20msec before the activation time, may be applied instead 680 msec after(assuming the cycle length is 700 msec).

Other applications of electric fields can increase the conductionvelocity, especially where the con on velocity is low as a result oftissue damage. Another method of controlling conduction is to apply anelectric field similar to that used for defibrillation. When appliedduring the repolarization period of these cells, this type of electricfield delays the repolarization. During this delayed/extendedrepolarization the cells are non-excitable. It should be appreciatedthat if this “defibrillation field” is applied using the techniquesdescribed herein (small, local and synchronized to a local activationtime) the heart itself will not be defibrillated by the electric field.In one preferred embodiment of the invention, a locally defibrillatedportion of the heart is isolated, by fences, from the rest of the heart.

FIG. 3 illuminates one use of extending the refractory periods ofcardiac tissue. Segment 40 is a portion of a right atrium. An activationsignal normally propagates from an SA node 42 to an AV node 44. Severalcompeting pathways, marked 46A-46D, may exist between SA node 42 and AVnode 44, however, in healthy tissue, only one signal reaches AV node 44within its excitability window. In diseased tissue, several signalswhich have traveled in different paths may serially excite AV node 44even though they originated from the same action potential in the SAnode. Further, in atrial fibrillation, the entire right atrium may haverandom signals running through it. In a preferred embodiment of theinvention, electric fields are applied to a plurality of regions whichact as “fences” 48A and 48B. These fences are non-conducting toactivation signals during a particular, predetermined critical time,depending on the activation time of the electric fields. Thus, theactivation signal is fenced in between SA node 42 and AV node 44. It isknown to perform a surgical procedure with a similar effect (the “maze”procedure), however, in the surgical procedure, many portions of theright atrium need to be ablated to produce permanent insulating regions(fences). In the present embodiment of the invention, at least portionsof fences 48A and 48B may be deactivated after the activation signal haspassed, so that the atrium can contract properly.

In a preferred embodiment of the invention, a fence is applied using alinear array of bipolar electrodes. In another preferred embodiment ofthe invention, a fence is applied using two (slightly) spaced apartelongate wire electrodes of opposite polarity. Preferably, portions ofthe wire electrodes are isolated, such as segments 0.5 cm long beingisolated and segments 0.5 cm long being exposed.

Still another preferred embodiment of the invention relates to treatingventricular fibrillation (VF). In VF, a ventricle is activated by morethan one activation signal, which do not activate the ventricle in anorderly fashion. Rather, each segment of the ventricle is randomlyactivated asynchronously with the other segments of the ventricle andasynchronously with the cardiac cycle. As a result, no pumping action isachieved. In a preferred embodiment of the invention, a plurality ofelectrical fences are applied in the affected ventricle to damp thefibrillations. In general, by changing the window during which segmentsof the ventricle are sensitive to activation, a fibrillation causingactivation signal can be blocked, without affecting the naturalcontraction of the ventricle. In one embodiment of the invention, thefences are used to channel the activation signals along correctpathways, for example, only longitudinal pathways. Thus, activationsignals cannot move in transverse direction and transverse activationsignals will quickly fade away, harmlessly. Healthy activation signalsfrom the AV node will not be aversely affected by the fences.Alternatively or additionally, fences are generated in synchrony withthe activation signal from the AV node, so that fibrillation causingactivation signals are blocked. Further alternatively, entire segmentsof the ventricle are desensitized to the activation signals by applyinga positive potential to those segments deemed sensitive to fibrillation.

Dividing the heart into insulated segments using fences is useful fortreating many types of arrhythmias. As used herein, the term insulatedmeans that conduction of the activation signal is blocked or slowed downor otherwise greatly reduced by deactivating portions of the heartconduction system. For example, many types of ventricular tachycardia(VT) and premature beats in the heart are caused by local segments oftissue which generate a pacing signal. These segments can be insulatedfrom other segments of the heart so that only a small, local segment isaffected by the irregular pacing. Alternatively, these diseased segmentscan be desensitized using an electric field, so that they do notgenerate incorrect activation signals at all.

Premature beats are usually caused by an oversensitive segment of theheart. By applying a local electric field to the segment, thesensitivity of the segment can be controlled and brought to similarlevels as the rest of the heart, solving the major cause of prematurebeats. This technique is also applicable to insensitive tissues, whichare sensitized by the application of a local electric field so that theybecome as sensitive as surrounding issues.

It should be appreciated that it is not necessary to know the exactgeometrical origin of an arthythmia to treat it using the abovedescribed methods. Rather, entire segments of the heart can bedesensitized in synchrony with the cardiac cycle so that they do notreact before the true activation signal reaches them. Further, the heartcan be divided into isolated segments or fenced in without mapping theelectrical system of the heart. For example, electrodes can be insertedin the coronary vessels to create fences in the heart. These fences canblock most if not all of the irregular activation signals in the heartand still allow “correct” activation signals to propagate bysynchronizing the generation of these fences to the “correct” cardiacactivation profile. Alternatively or additionally, each isolated segmentis paced with an individual electrode. Alternatively, an array ofelectrodes may be implanted surrounding the heart so that it is possibleto individually control substantially any local portion thereof.

In an additional preferred embodiment of the present invention, segmentsof the heart are continuously controlled using an electric field, sothat their membrane potential at rest is below −60 mV. Below this level,the voltage-gated sodium channels cannot be opened by an activationsignal. It is not usually possible to clamp all of the cells in a tissuesegment to this voltage, so some of the cells in the tissue willtypically be excitable. However, it is known that hyperpolarizationcauses depletion of potassium ions in the extracellular spacessurrounding individual cardiac muscle cells, which will cause a generalreduction in the excitability of all the cells which share the sameextracellular spaces. As described, for example, in “K+ Fluctuations inthe Extracellular Spaces of Cardiac Muscle: Evidence from the VoltageClamp and Extracellular K+—Selective Microelectrodes”, Cohen I and KlineR. Circulation Research, Vol. 50, No. 1, pp. 1-16, January 1982, thedisclosure of which is incorporated herein by reference. Thus, thereaction of the segments of the heart to an activation signal isreduced, has a longer delay and the propagation velocity in thosesegments is significantly reduced. Other resting potentials may affectthe opening of other voltage-gated channels in the cell.

Another preferred embodiment of the invention relates to cardiacsurgery. In many instances it is desirable to stop the pumping action ofthe heart for a few seconds or minutes necessary to complete a suture ora cut or to operate on an aneurysm. Current practice is not veryflexible. In one method, the heart is bypassed with a heart-lung machineand the heart itself is stopped for a long period of time. This processis not healthy for the patient as a whole or for the heart itself and,often, serious post-operative complications appear. In another method,the heart is cooled down to reduce its oxygen consumption and it is thenstopped for a (non-extendible) period of a few minutes. The period isnon-extendible in part since during the stoppage of the heart the entirebody is deprived of oxygen. In these methods, the heart is usuallystopped using a cardioplesic solution. In a third method fibrillation isinduced in the heart. However, fibrillation is known to cause ischemia,due to the greatly increased oxygen demand during fibrillation and theblockage of blood flow in the coronary arteries by the contraction ofthe heart muscle. Ischemia can irreversibly damage the heart.

Cessation or reduction of the pumping activity of the heart may beachieved using methods described herein, for example, fencing. Thus, ina preferred embodiment of the invention, the pumping action of the heartis markedly reduced using techniques described herein, repeatedly andreversibly, for short periods of time. It should be appreciated that dueto the simplicity of application and easy reversibility, stopping theheart using electrical control is more flexible than currently practicedmethods. Electrical control is especially useful in conjunction withendoscopic heart surgery and endoscopic bypass surgery, where it isdesirable to reduce the motion of small segments of the heart.

Another preferred embodiment of the present invention relates totreating ischemic portions of the heart. Ischemic portions, which may beautomatically identified from their injury currents using locallyimplanted sensors or by other electro-physiological characterization,may be desensitized or blocked to the activation signal of the heat.Thus, the ischemic cells are not required to perform work and may beable to heal.

U.S. Provisional Application No. 60/009,769, filed Jan. 11, 1996,entitled “Cardiac Electromechanics” by Shlomo Ben-Haim and MaierFenster, now expired, and its corresponding Israeli Patent ApplicationNo. 116,699 titled “Cardiac Electromechanics”, filed on Jan. 8, 1996byapplicant Biosense Ltd., now Israeli Patent No. 116,699, the disclosuresof which are incorporated herein by reference, describe methods ofcardiac modeling and heart optimization. In cardiac modeling, thedistribution of muscle mass in the heart is changed by changing theworkload of segments of the heart or by changing the plateau duration ofaction potentials at segments of the heart. These changes may beachieved by changing the activation profile of the heart. Plateauduration can be readily controlled using methods as describedhereinabove. Further, by controlling the conduction pathways in theheart, according to methods of the present invention, the entireactivation profile of the heart can be affected. In cardiac optimizationas described in these applications, the activation profile of the heartis changed so that global parameters of cardiac output are increased.Alternatively, local physiological values, such as stress, areredistributed to relieve high-stress locations in the heart. In apreferred embodiment of the present invention, the activation profilemay be usefully changed using methods as described hereinabove.

In order to best implement many embodiments of the present invention, itis useful to first generate an electrical, geometrical or mechanical mapof the heart. U.S. patent application Ser. No. 08/595,365 entitled“Cardiac Electromechanics”, filed on Feb. 1, 1996 by Shlomo Ben-Haim,now U.S. Pat. No. 5,738,096 and two PCT applications filed in Israel, oneven date as the instant application, by applicant “Biosense” and titled“Cardiac Electromechanics”, published as WO 1997/024981 and “MappingCatheter”, published as WO 1997/024983, the disclosures of which areincorporated herein by reference, describe maps and methods and meansfor generating such maps. One particular map which is of interest is aviability map, in which the viability of different segments of hearttissue is mapped so as to identify hibernating and/or ischemic tissue.U.S. Pat. No. 5,391,199, U.S. patent application Ser. No. 08/293,859,filed on

Aug. 19, 1994, titled “Means and Method for Remote Object Position andOrientation Detection System” now abandoned, and PCT Patent ApplicationNo. US 1995/01103, published as WO 1996/05768 on Feb. 29, 1996, thedisclosures of which are incorporated herein by reference, describeposition sensing means suitable for mounting on a catheter which isespecially useful for generating such maps. Such position sensing meansmay also be useful for correctly placing electrodes in the heart if theelectrodes are implanted using minimally invasive techniques such asthose using endoscopes, throactoscopes and catheters.

In one preferred embodiment of the invention, a map of the heart is usedto determine which portions of the heart are viable, and thus, can becontrolled to increase the cardiac output. Preferably, the entireactivation profile of the heart is taken into account when determiningto which portions of the heart a controlling field should be applied, tomaximize a parameter of cardiac output. The activation profile may alsodetermine the timing of the application of the field. A perfusion mapmay be used to access the blood flow to various portions of the heart.It is to be expected that increasing the contractility of a segment ofheart muscle also increases the oxygen demand of that segment.Therefore, it is desirable to increase the contractility only of thosesegments which have a sufficient blood flow. Possibly, the oxygendemands of other segments of the heart is reduced by proper controllingof the activation sequence of the heart.

Alternatively or additionally to mapping the perfusion and/or viabilityof the heart, the onset of controlling the heart may be performedgradually. Thus, the cardiac blood supply has time to adapt to theincreased demand (if any) and to changes in supply patterns. Inaddition, the increase in demand will not be acute, so no acute problems(such as a heart attack) are to be expected as a result of thecontrolling. In one embodiment, the controlling is applied, at first,only every few heart beats, and later, every heart beat. Additionally oralternatively, the duration of a controlling pulse is graduallyincreased over a long period of time, such as several weeks.Additionally or alternatively, different segments are controlled fordifferent heart beats, to spread the increased demand over a largerportion of the heart.

In an alternative preferred embodiment of the invention, thecontractility of the heart is controlled only during the day and notduring the night, as the cardiac demand during the day time is typicallygreater than during the night. Alternatively or additionally, thecontroller is used for a short time, such as 15 minutes, in the morning,to aid the patient in getting up. Alternatively or additionally, acontrolling electric field is applied only once every number of beats(day and/or night). Further alternatively, the heart is controlled for ashort period of time following an acute ischemic event, until the heartrecovers from the shock. One preferred controlling method which may beapplied after a heart attack relates to preventing arrhythmias. Anotherpreferred controlling is desensitizing infarcted tissue or reducing thecontractility of such tissue or electrically isolating such tissue so asto reduce its oxygen demands and increase its chance of healing.

One benefit of many embodiments of the present invention, is that theycan be implemented without making any structural or other permanentchanges in the conduction system of the heart. Further, many embodimentsmay be used in conjunction with an existing pacemaker or in conjunctionwith drug therapy which affects the electrical conduction in the heart.In addition, different controlling schemes may be simultaneouslypracticed together, for example, controlling the heart rate andincreasing contractility in the left ventricle.

It must be appreciated however, that, by changing the activation profileof the heart, some changes may be effected on the structure of theheart. For example, cardiac modeling, as described above, may resultfrom activation profile changes, over time.

FIG. 4A is a schematic diagram of an electrical controller 50, inoperation, in accordance with a prefer embodiment of the invention. Amuscle segment 56, which is controlled by controller 50, is preferablyelectrified by at least one electrode 52 and preferably by a secondelectrode 54. Electrode 54 may be electrically floating. A sensor 58 maybe used to determine the local activation time of segment 56, as aninput to the controller, such as for timing the electrification of theelectrodes. Other additional or alternative local and/or global cardiacparameters may also be used for determining the electrification of theelectrodes. For example, the electrode(s) may be used to sense the localelectrical activity, as well known in the art. Alternatively, sensor 58is located near the SA node for determining the start of the cardiacrhythm. Alternatively, sensor 58 is used to sense the mechanicalactivity of segment 56, of other segments of the heart or for sensingthe cardiac output. Cardiac output may be determined using a pressuresensor or a flow meter implanted in the aorta. In preferred embodimentof the invention, sensor 58 senses the electrical state of the heart,controller 50 determines a state of fibrillation and electrifieselectrodes 52 and 54 accordingly.

Sensor 58 may be used for precise timing of the electrification ofelectrodes 52 and 54. One danger of incorrect electrification of theelectrodes is that if the electrodes are electrified before anactivation front reaches segment 56, the electrification may inducefibrillation. In a preferred embodiment of the invention, sensor 58 isplaced between electrodes 52 and 54 so that an average activation timeof tissue at the two electrodes is sensed. It should be appreciated thatthe precise timing of the electrification depends on the propagationdirection of the activation front in the heart. Thus, if tissues atelectrodes 52 and 54 are activated substantially simultaneously, thecontrolling field can be timed to be applied shortly thereafter.However, if tissue at one electrode is activated before tissue at theother electrode, the delay time in electrifying the electrodes must belonger. Thus, the optimal delay time in electrifying an electrode afterthe local activation time is dependent, among other things, on theorientation of the electrodes relative to the activation front. Theconduction velocity of the activation front is affected in a substantialmanner by the orientation of the cardiac muscle fibers. Thus, theorientation of the electrodes relative to the muscle fiber directionalso has an effect on the optimal delay time.

In another preferred embodiment of the invention, local activation time(and electrification of electrodes 52 and 54) is estimated, based on aknown propagation time of the activation signal. For example, if sensor58 is placed in the right atrium, a delay of about 120 msec may beexpected between the sensing of an activation signal at sensor 58 andthe arrival of the activation signal at electrodes 52 and 54. Suchdelays can also be estimated. Within a single chamber, for example, ittakes about 30-50 msec for the activation front to cover all the leftventricle. A sensor 58 may be placed at a location in the left ventriclewhich is excited relatively early by the activation signal. In apreferred embodiment of the invention, activation propagation timesbetween implanted sensors and electrodes are measured in at least oneheart activation profile (such as at a resting heart rate) and are usedto estimate a desired delay in electrification of electrodes. It shouldbe appreciated that, in diseased hearts, local conduction velocity maychange substantially in time, thus, learning of and adaptation to thechanges in local activation are a desire characteristic of controller50. In a preferred embodiment of the invention, a particular state ofarthythmia (or activation profile) is determined based on a parameter ofthe ECG, such as the morphology and/or the frequency spectrum of eitheran external or an internal ECG. Controller 50 determines the controllingprofile based on the determined state. In particular, delay times, asdescribed herein, may be associated with states, so that the exact delaytime for the activation may be decided in real-time for each state ofarthythmia. Preferably, the delay times are precalculated and/or aredetermined during a learning state of controller 50, in which stage, onoptimal delay time is determined for a particular activation state andstored in association therewith.

Sensor 58 may be placed on the epicardium, on the endocardium or, in apreferred embodiment of the invention, sensor 58 is inserted into themyocardium.

FIG. 4B shows an alternative embodiment of the invention, wherein aheart segment 55 is controlled by a plurality of electrodes 59 which areconnected to a controller 57. The use of many electrodes enables greatercontrol of both spatial and temporal characteristics of the appliedelectric field. In one example, each one of electrodes 59 is used todetermine its local activation. Controller 57 individually electrifieselectrodes 59 according to the determined activation. Preferably, theelectrodes are activated in pairs, with current flowing between a pairof electrodes whose local activation time is known.

Different embodiments of the present invention will typically requiredifferent placement of the control electrodes. For example, someembodiments require a large area electrode, for applying an electricfield to a large portion of the heart. In this case, a net typeelectrode may be suitable. Alternatively, a large flat electrode may beplaced against the outside of the heart. Other embodiments require longelectrodes, for example, for generating fences. In this case, wires arepreferably implanted in the heart, parallel to the wall of the heart.Optionally, the electrodes may be placed in the coronary vessels outsidethe heart. In some aspects of the invention electrodes are placed sothat the field generated between the electrodes is parallel to thedirection in which activation fronts normally propagate in the heart, inothers, the field is perpendicular to such pathways.

In one preferred embodiment of the invention, a pacemaker is providedwhich increases the cardiac output. A pacemaker activation pulse isusually a single pulse of a given duration, about 2 msec in an internalpacemaker and about 40 msec in an external pacemaker. In accordance witha preferred embodiment of the invention, a pacemaker generates a doublepulse to excite the heart. A first portion of the pulse may be astimulation pulse as known in the art, for example, 2 mA (milliamperes)constant current for 2 msec. A second portion of the pulse is a pulse asdescribed herein, for example, several tens of msec long and at a shortdelay after the first portion of the pacemaker pulse. Alternatively, avery long stimulation pulse may be used. This type of pacemakerpreferably uses two unipolar electrodes, one at the apex of the heartand one at the top of the left ventricle (or the right ventricle if itthe right ventricular activity is to be increased).

In a preferred embodiment of the invention, a controller is implantedinto a patient in which a pacemaker is already implanted. The controlleris preferably synchronized to the pacemaker by connecting leads from thecontroller to the pacemaker, by sensors of the controller which sensethe electrification of the pacemaker electrodes and/or by programming ofthe controller and/or the pacemaker.

In a preferred embodiment of the invention, the pacemaker adapts to thephysiological state of the body in which it is installed by changing theheart's activity responsive to the physiological state. The pacemakercan sense the state of the body using one or more of a variety ofphysiological sensors which are known in the art, including, pH sensors,pO₂ sensors, pCO₂ sensors, blood-flow sensors, acceleration sensors,respiration sensors and pressure sensors. For example, the pacemaker canincrease the flow from the heart in response to an increase in pCO₂.Since the control is usually applied in a discrete manner over a seriesof cardiac cycles, this control may be termed a control sequence. Themodification in the heart's activity may be applied gradually or,preferably, in accordance with a predetermined control sequence.

In one aspect of the invention, target values are set for at least oneof the measured physiological variables and the pacemaker monitors thesevariables and the effect of the control sequence applied by thepacemaker to determine a future control sequence. Once the discrepancybetween the target value and the measured value is low enough, thecontrol sequence may be terminated. As can be appreciated, one advantageof a cardiac controller over a pacemaker is that it can control manyaspect of the heart's activation profile. As a result, the controllercan determine a proper tradeoff between several different aspects of theactivation profile of the heart including, heart output, oxygenation ofthe cardiac muscle, contractile force of the heart and heart rate.

Another aspect of the invention relates to modifying the relationbetween the contraction of the left ventricle an the contention of theright ventricle. In a healthy heart, increased contractility of the leftventricle is followed by increased contractility of the right ventricle,as a result of the increased output of the left ventricle, which causesan increase in the preload of the right ventricle. Decreased leftventricular output reduces the right ventricular output in a similarmanner. In some cases, such as pulmonary edema, it may be desirable tomodify the flow from one ventricle without a corresponding change in theflow from the other ventricle. This may be achieved by simultaneouslycontrolling both ventricles, one control increasing flow from oneventricle while the other control decreases the flow from the otherventricle. This modification will usually be practiced for short periodsof time only, since the vascular system is a closed system and, in thelong run, the flow in the pulmonary system is the same as in the generalsystem. In a preferred embodiment of the invention, this modification ispracticed by controlling the heart for a few beats, certain certinperiod of time.

Another aspect of the present invention relates to performing a completesite of therapies using a single device. A controller in accordance withpreferred embodiment of the invention includes several therapies whichit can apply to the heart, including for example, increasingcontractility, defibrillation, fencing, heart rate control and pacing.The controller senses (using physiological sensors) the state of thebody and decides on an appropriate short-term therapy, for example,defibrillation to overcome fibrillation the heart rate to increase thecardiac outflow or applying fences to test a sudden arthythmia.Additionally or alternatively, such a controller can change the appliedcontrol sequence in response to long term therapeutic goals. Forexample, if increasing contractility is used to increase the muscle massin a portion of the heart, once a required muscle mass is reached, thecontrol sequence may be stopped. This is an example of a therapeutictreatment affected by the controller. In another example, a few weeksafter the device is implanted and programmed to increase the cardiacoutput to a certain target variable, the target variable may be changed.Such a change may be mandated by an expected period of time over whichthe heart adapts to the controller. One such adaptation is that theheart becomes stronger and/or more efficient. Another such adaptationmay be that the heart reduces its response to the control sequence, sothan a different control sequence may be required to achieve the samegoals. In a preferred embodiment of the invention, the control sequenceis varied every certain period of time and/or when response of the heartto the control sequence is reduced below a predetermined level.

In an alternative embodiment of the invention a control device includesa human operator in the loop, at least during a first stage where thecontroller must “learn” the distinctive aspects of a particularheart/patient. At a later stage, the operator may monitor thetherapeutic effect of the controller on a periodic basis and change theprogramming of the controller if the therapeutic effect is not thatwhich the operator desires.

In an additional embodiment of the invention, the controller is notimplanted in the body. Preferably, the control sequence is applied usingone or more catheters which are inserted into the vascular system.Alternatively, electrodes may be inserted directly through the chestwall to the heart.

In another preferred embodiment of the invention, a controlling current(or electric field) is applied from electrodes external to the body. Oneinherent problem in external controlling is that the controlling currentwill usually electrify a large portion of the heart. It thereforeimportant to delay the application of the current until the heart isrefractory. One method of achieving this objective is to sense the ECGusing external electrodes. Preferably, an electrode array is used sothat a local activation time in predetermined portions of the heart maybe determined.

Another method of external controlling combines controlling withexternal pacing, thereby simplifying the task of properly timing thecontrolling pulse relative to the pacing pulse. In a preferredembodiment of the invention, the delay between the pacing pulse and thecontrolling pulse is initially long and is reduced until an optimumdelay is determined which gives a desired improvement in pumping anddoes not cause fibrillation.

Additionally or alternatively, the external pacemaker includes adefibrillator which applies a defibrillation pulse if the controllingpulse causes fibrillation.

It should be appreciated that pacemakers and controllers in accordancewith various embodiments of the present invention share many commoncharacteristics. It is anticipated that combining the functions of acontroller and of a pacemaker in a single device will have many usefulapplications. However, several structural differences betweenpacemakers, defibrillators and controllers in accordance with manyembodiments of the present invention are notable.

One structural difference relates to the size and shape of theelectrodes. Pacemakers usually use bipolar activation electrodes orunipolar electrodes where the pacemaker case is the other electrode. Thedesign of the electrodes is optimized to enhance the contact between theelectrodes and the heart at a small area, so that the power drain in thepacemaker will be as low as possible. In a defibrillator, there is anopposite consideration, namely, the need to apply a very large amount ofpower to large areas of the heart without causing damage to the heart.In preferred embodiment of the present invention, small currents areapplied, however, it is desirable that the current will flow throughlarge portions of the cardiac tissue, in a controlled manner.

Another structural difference relates to the power supply. Pacemakerpower supplies usually need to deliver a short (2 msec), low power,pulse once a second. Defibrillators usually need to deliver a short (6-8msec), high power, pulse or series of pulses at long intervals (days).Thus, pacemakers, usually drain the power from a capacitor having ashort delay and which is directly connected to the battery, whiledefibrillators usually charge up both a first and a second capacitor sothat they may deliver two sequential high-power pulses. A controller inaccordance with some embodiments of the present invention, is requiredto provide a long low power pulse once a second. Preferably, the pulseis longer than 20 msec, more preferably longer than 40 msec and stillmore preferably, longer than 70 msec. Such a pulse is preferablyachieved using a slow-decay capacitor and/or draining the power directlyfrom a battery, via an constant current, a constant voltage and/or asignal forming circuit. Preferably, the electrodes used in a controllerin accordance with the present invention slowly release a steroid, toreduce inflammation at the electrodes point of contact with the heart.

Another structural difference relates to the placement of theelectrodes. In a pacemaker, a single electrode is placed in the apex ofthe heart (in some pacemakers, one electrode per chamber, or sometimesmore than one). In a defibrillator, the electrodes are usually placed sothat most of the heart (or the right atrium in AF defibrillators) isbetween the electrodes. In a controller according to some embodiments ofthe present invention, the electrodes are placed across a segment ofheart tissue, whose control is desired. Regarding sensing, manypacemakers utilize sensing in one chamber to determine a proper delaybefore electrifying a second chamber. For example, in a heart whose AVnode is ablated, the left ventricle is synchronized to the right atriumby a pacemaker which senses an activation front in the right atrium andthen, after a suitable delay, paces the left ventricle. It is not,however, a usual practice to sense the activation front in a chamber andthen pace the selfsame chamber after a delay. Even when such samechamber sensing and pacing is performed, the sensing and pacing areperformed in the right atrium and not the left ventricle. Further,sensing at the pacing electrode in order to determine a delay time forelectrification of the electrode is a unique aspect of some aspects ofthe present invention, as is sensing midway between two pacingelectrodes. Another unique aspect of some embodiments of the presentinvention is pacing in one chamber (the right atrium), sensing an effectof the pacing in another chamber (the left ventricle) and then pacingthe other chamber (the left ventricle). The use of multiple pairs ofelectrodes disposed in an array is another unique aspect of certainembodiments of the present invention.

Due to the wide range of possible signal forms for a controller, apreferred controller is programmable, with the pulse form beingexternally downloadable from a programmer. Telemetry systems for one-and two-directional communication between an implanted pacemaker and anexternal programmer are well known in the art. It should be noted, thatvarious embodiments of the present invention can be practiced, albeitprobably less efficiently, by downloading a pulse form in accordancewith the present invention to a programmable pacemaker. In a preferredembodiment of the invention, such a programmer includes software foranalyzing the performance and effect of the controller. Since analysisof the performance of the controller may include information notprovided by the controller, such as an ultrasound image or an externalbody ECG, such software may be run from a separate computer.

It should be appreciated that a controller in accordance with thepresent invention is preferably personalized for particular patientbefore implantation therein. Alternatively or additionally, thepersonalizations may be performed by programming the device after it isimplanted. The heart of the patient is preferably mapped, as describedabove, in order to determine the preferred placement of the controlelectrodes and/or the sensing electrodes and/or in order to determinethe proper timings.

In one example, where the left ventricle is controlled, it is useful todetermine the earliest activated area in the left ventricle, forimplantation of the sensing electrode. In another example, the heart ismapped to determine viable tissue portions which are suitable forimplantation of electrodes (such that current will flow between the twoelectrodes). In another example, the activation profile of the heart isdetermined so that it is possible to estimate propagation times betweenvarious portions of the heart, and in particular, the pacing source(natural or artificial) and the controlling electrodes. In anotherexample, the propagation of the activation front in the heart isdetermined so that the proper orientation of the electrodes with respectto the front may be achieved and/or to properly locate the sensingelectrode(s) with respect to the controlling electrodes. It is alsouseful to determine arrhythmias in the heart so as to plananti-arrhythmic treatment in accordance with the present invention.

In another example, the amount of increase in contractility isdetermined by the amount of live tissue between the controllingelectrodes. A viability map may be used to determine a segment of hearttissue having a desired mount of live tissue.

The timing of the activation of cardiac muscle relative to the rest ofthe heart is an important factor in determining its contribution to thecardiac output. Thus, it is useful to determine the relative activationtime of the segment of the heart which is to be controlled, prior toimplanting the electrodes.

FIG. 5 shows an experimental setup designed and used to test someembodiments of the present invention. A papillary muscle 60, from amammalian species (in the first set of experiment, a guinea pig) wasconnected between a support 62 and a pressure transducer 64 in a mannersuch that isometric contraction could be achieved. Muscle 60 wasstimulated by a pair of electrodes 66 which were connected to a pulsedconstant current source 70. A pulse generator 74 generated constantcurrent pacing pulses for electrodes 66. A pair of electrodes 68 wereused to apply an electric field to muscle 60. A slave pulse generator76, which bases its timing on pulse generator 74, electrified electrodes68 via a pulsed constant current source 72. The force applied by themuscle was measured by transducer 64, amplified by an amplifier 78 anddrawn on a plotter 80. Pulse generator 74 selectably generated shortactivation pulses 500, 750, 1000 and 1500 msec (t1) apart for variableactivation of muscle 60, i.e., 2, 1.33, 1 and 0.66 Hz. Pulse generator76 generated a square wave pulse which started t2 seconds after theactivation pulse, was t3 seconds long and had a selected current (in mA)higher than zero (in amplitude).

FIG. 6A-6C are graphs showing some results of the experiments. Ingeneral, the results shown are graphs of the force of the musclecontractions after muscle 60 reaches a steady state of pulsedcontractions. FIG. 6A is a graph of the results under the followingconditions:t1 pacemaker pulse)=750 msec;t2 (delay)=150 msec;t3 (pulse duration)=100 msec; andcurrent=10 mA.

As can be seen, the force exerted by the muscle was increased by afactor of 2.5 when the controlling pulse (electrodes 68) was used asopposed to when electrodes 68 were not activated.

FIG. 6B is a graph of the force of muscle contractions under thefollowing conditions:t1=1000 msec;t2=20 msec;t3=300 msec; andcurrent 7.5 mA.As can be seen, the amplitude of the connections is extremelyattenuated. When the polarity of the controlling signal was inverted,after a few contractions, the contractions of muscle 60 were almostcompletely attenuated.

FIG. 6C is a graph of the force of muscle contractions under thefollowing conditions:t1=1000 msec;t2=20 msec;t3=300 msec; andcurrent=1 mA.In this case, the effects of increasing the contractile force of muscle60 remained for about two minutes after the electrification ofelectrodes 68 was stopped. Thus, the contraction of muscle 60 isdependent not only on the instantaneous stimulation and control but alsoon prior stimulation and control.

Using a similar experimental setup, additional experiments wereperformed, some on papillary muscles and some on cardiac septum musclesfrom the ventricles and atria walls. In these experiments, the testanimal was usually a rabbit, however, in one case a rat was used. Mostof these experiments used a DC constant current source which was incontact with the muscle, however, an electrical field scheme was alsotested and yielded similar results. In the electric field scheme, theelectrodes were placed in a solution surrounding the muscle segment andwere not in contact with the muscle segment. The current used was 2-10mA. In a few experiments, no increase in contractile force was induced,however, this may be the result of problems with the electrodes(interaction with ionic fluids) and/or the current source, especiallysince Ag—AgO electrodes, which tend to polarize, were used in theseexperiments. In general, many cycles of increases in contractility andreturn to a base line were performed in each experiment. In addition,the increases in contractility were repeatable in subsequentexperiments. These increases were obtained over a pacing range of 0.5-3Hz.

FIGS. 7A-7C summarize the results obtained in these further experiments.It should be appreciated, that the time scales of the applied pulse arestrongly associated with the pacing rate and with the animal species onwhich the experiment was performed. In these experiments, the pacingrate was usually about 1 Hz. Within the range of 0.5-3 Hz the pulse formrequired for an increase in contraction force is not substantiallyaffected by the pacing rate. The intensities of the currents used in theexperiments are affected by the electrode types used, and possibly bythe animal species, so that if other electrode types are used, differentcurrent intensities may be required for the same effect. Ten experimentswere performed on a left papillary muscle, of which 8 showed an increasein contractility due to an applied non-excitatory current. Fourexperiments were performed on a right papillary muscle, of which threeshowed an increase in contractility. Two experiment were performed onleft ventricular muscle, both showed an increase in contractility. Onthe average, an increase in contractile force of ˜75% was obtained. Therange of increases was between 43% and 228% depending on the exactexperimental configuration.

FIG. 7A shows the effect of a delay in the onset of the applied currenton the increase in contractile force. A small delay does notsubstantially affect the increase in contractile force. It should benoted that as the delay increases in duration, the increase incontractility is reduced. It is theorized that such a pulse, applied atany delay, affects the plateau and/or the refractory period. However,the increase in contractility is only possible for a window of timewhich is more limited than the entire activation cycle of a musclefiber.

Changing the polarity of the applied current sometimes affected thecontractility. Usually, a first polarity generated an greater increasein contractile force, while the other polarity generated a lowerincrease than the first polarity. In some experiments, reversing thepolarity during an experiment decreased the contractile force, for ashort while or for the entire duration of the pulse, to a level lowerthan without any applied current. One possible explanation is thatpapillary muscle has a preferred conduction direction (which may not beas pronounced in ventricular tissue). Another explanation is artifactsrelating to the ionization of the electrodes used in the experiments.

FIG. 7B shows the effect of pulse duration on the increase incontractile force of a papillary muscle. A very short pulse on the orderof 1 msec, does not substantially affect the contractile force. In apulse between about 1 msec and 20 msec the contractility increases withthe duration. In a pulse of over 20 msec, the increase in contractileforce as a function of pulse duration is reduced; and in a pulse withover about 100 msec duration there is no apparent further increase inthe contractile force of an isolated papillary muscle.

FIG. 7C shows the effect of the current intensity on the increase incontractile force. It should be noted that above about 8 mA thecontractile force actually decreases below the baseline condition (whereno current was applied). It may be that this effect is related to theabove described theory of intra-cellular calcium stores, and that toomuch calcium in the cardiac muscle cell reduces the availability ofthese stores, and therefore, the cell's contractility.

In addition to the above summarized results, several experimentalresults deserve special notice.

In one experiment, shown in FIG. 8A, a segment of a right atrium from arabbit was allowed to set its own, intrinsic, pace (˜2-3 Hz). Anon-excitatory current which was a constant current of 2 mA was driventhrough the tissue, constantly, as shown. As a result, the self pacingrate of the segment increased, as did the contractility (after a first,short, reduction in force).

In a second, multi-step experiment, a right rabbit papillary muscle waspaced at 1.5 Hz. The applied current was constant at between 2 and 4 mA(depending on the experimental step), in a pulse 70 msec long and nodelay after the pacemaker pulse. The contractility increased by between45% and 133% (depending on the step). The increased contractility wassustained at 3 mA for as long as two hours. Stopping the applied fieldcaused a rapid return to the original (uncontrolled) contractile force.Re-application of the field repeated the previous results.

In a third experiment, increasing the pulse duration of a 2 mA currentover the range 10 to 100 msec in a left rabbit papillary muscleincreased the contractile force; however, no effect on the duration ofthe muscle twitch was observed.

FIG. 8B is a series of graphs which shows an increase in contractilityin several different cardiac muscle types (the horizontal bar indicatesthe application of a controlling electric field).

Two more experiments, not included in the above discussion, wereperformed on a papillary muscle. In these experiments, a triangularshaped pulse, having a duration of 120 msec and a peak of 5 mA, wasapplied with no delay after a standard pacing pulse (2 mA, 2 msec). Theincrease in contractility of the muscle was ˜1700%, from 10 mg to 178mg. The is duration of the contraction increased from 220 msec to 260msec.

In another series of experiments, a whole living heart was removed froma rabbit (1-2 Kg in weight) and controlled using methods as describedhereinabove. The apparatus for keeping the heart alive was an IsolatedHeart, size 5, type 833, manufactured by Hugo Sachs Elektronik,Gruenstrasse 1, D-79232, March-Hugstetten, Germany. In theseexperiments, only the left ventricle is functional. The Pulmonary veinsare connected to a supply hose, in which supply hose there is a warm(˜37° C.) isotonic, pH balanced and oxygenated solution. The solution ispumped by the heart into the aorta. The heart itself is supplied withoxygen from the aorta, through the coronary arteries. The coronary veinsempty into the right ventricle, from which the solution drips out. Thesolution which drips out (coronary blood flow) can be measured bycollecting it in a measuring cup. Both the preload and the afterload ofthe vascular system can be simulated and preset to any desirable value.In addition, the afterload and preload can be measured using thisapparatus.

The heat was connected to an ECG monitor, a pacemaker and a programmablepulse generator. The electrodes for applied the field typically had anarea of between 2 and 3 cm². The left ventricular pressure (LVP) wasmeasured using a pressure probe inserted into the ventricle. The flowthrough the aorta was measured using an electro-magnetic flowmeter.Various parameters, such as pH, pO₂, pCO₂ and temperature may bemeasured by attaching additional measurement devices. All themeasurement devices may be connected to a computer which collects, andpreferably analyzes the results.

A most notable experimental result was an increase in flow from theheart as a result of electrical control. Another notable result was anincrease in afterload as a result of the control. Still another notableresult was an increase in the developed left ventricular pressure, inthe heart, when electrical control was applied.

A summary of 26 experiments using an isolated heart is as follows, in 20experiments an increase in cardiac output was observed, while in sixexperiments, no increase in cardiac output was observed. Possiblereasons for the failure to increase cardiac output include, biologicaldamage to the heart while it was being extracted from the animal. Insome cases, this damage is clear from the reduced cardiac output in oneisolated heart as compared to a second, otherwise similar, rabbit heart.Other reasons include, incorrect placement of electrodes (over the rightventricle instead of over the left ventricle), encrustation of theelectrodes with proteins and technical problems with the equipment whichdelivers the controlling electric field. In 11 experiments where theleft ventricle was paced, the average increase in cardiac output was 17%with a standard deviation of 11%. In eight experiments where the rightatrium was paced, the average increase was 9±4%. In nine experiments,where the heart was not paced and a controlling field was applied basedon a sensing of local activation times, the increase was 7±2%. It shouldbe noted that the number of experiments is over 26, since in someexperiments two different pacing paradigms were tried.

FIG. 9 is a series of graphs showing the results of an experiment inwhich a 10 mA constant current pulse, having a duration of 20 msec anddelayed 5 msec after the pacing of the heart, was applied. Two wireelectrodes were used to apply this pulse, one electrode was placed atthe apex of the heart overlaying the left ventricle and one electrodewas placed at the base of the left ventricle. The pacing was preformedusing a bipolar electrode, also placed near the apex of the heart on theleft ventricle. The pacing rate was approximately 10% higher than thenormal pace. The pacing pulse was 2 msec long, 2 mA in amplitude and wasapplied at a frequency of ˜3.5 Hz. The application of the constantcurrent pulse is indicated in the Figure (and in the following ones) bya bar (filled or unfilled).

In this experiment, an increase in the afterload (the actual pressuredeveloping in the Aorta) of about 5% and an increase in LVP (Leftventricle pressure) of about 3% were obseeved. The increase in LVP wasonly in the end systole pressure, not in the end diastole pressure. Anincrease in flow of about 11% is clearly shown in FIG. 9. The increasein flow is very important since one of the main problems with patientswith congestive heart failure is a low cardiac flow.

FIG. 10 is a series of graphs showing the results of an experiment inwhich a 5 mA constant current pulse, having a duration of 80 msec anddelayed 2 msec after the pacing of the heart was applied. The wiring andpacing in this experiment were similar to the experiment described withreference to FIG. 9, except that carbon electrodes were used forapplying the constant current pulse.

In this experiment, a noticeable increase in afterload can be determinedfrom the graph. An increase in LVP (Left ventricle pressure) of about 6%can also be observed. It should be noted that the increase in afterloadis observed for both the diastolic pressure and the systolic pressure,while inside the left ventricle, the pressure increase is mainly in thesystole. In fact, there is a slight reduction in diastolic pressure,which may indicate an increase in contractility and/or an improvement indiastolic wall motion. An increase in flow of several hundred percent isclearly shown in FIG. 10. It should be noted that a healthy heart may beexpected to have a flow of about 100 ml/min. The low initial flow (12mi/min.) is probably a result of damage to the heart, such as ischemia.

FIG. 11 is a series of graphs showing the results of an experiment inwhich a 5 mA constant current pulse, having a duration of 20 msec anddelayed 2 msec after the local activation time at the ventricle wasused. The pacing and wiring in this experiment were similar to theexperiment described with reference to FIG. 9. A sensing electrode wasplaced on the left ventricle halfway between the two controllingelectrodes and the delay was measured relative to the local activationtie at the sensing electrode. The sensing electrode comprised two sideby side “J” shaped iridium-platinum electrodes. A pacing pulse wasapplied using an additional Ag—AgCl electrode at the apex of the heart.In this experiment, the sensing electrode is shut off for 200 msec afterthe local activation is sensed, so that the controlling pulse is noterroneously detected by the sensing electrode as a local activation.

In this experiment, an increase in the afterload and an increase in LVPwere observed. The increase LVP was only evident in the end systolepressure, not in the end diastole pressure. An increase in flow of about23% is clearly shown in FIG. 11.

FIG. 12 is a series of graphs showing experimental results from anotherexperiment, showing an significant increase in aortic flow and in aorticpressure. The pulse parameter were 5 mA, 70 msec duration and a 5 msecdelay. Pacing and wiring are as in the experiment of FIG. 9.

FIG. 13 is a series of graphs showing experimental results fromrepeating the experiment of FIG. 12, showing that the increase in aorticflow is controlled by the electrification of the electrodes. Thus, whenthe electrification is stopped, the flow returns to a baseline value;when the electrification is restarted the flow increases again and whenthe electrification is stopped again, the flow returns to the baselinevalue.

FIG. 14 is a series of graphs showing experimental results from anotherexperiment, in which the right atrium was paced at 3 Hz, rather than theleft ventricle being paced at 3.5 Hz, as in previously describedexperiments. Pacing and wiring are similar to those in the experiment ofFIG. 11, except that the pacing electrodes are in the right atrium andthe action potential is conducted from the right atrium to the leftventricle using the conduction pathways of the heart. The pulseparameters are 5 mA for 20 msec, with no delay after sensing a localaction potential. The sensing electrode is shut off for 100 msec afterit senses the local action potential, to reduce the possibility ofidentifying the controlling pulse as a local activation potential. Inthis experiment, an increase in flow of 9% was observed.

FIG. 15 is a series of graphs showing experimental results from anotherexperiment, similar to the experiment of FIG. 14, except hat instead ofusing two controlling electrodes, four controlling electrodes were used.The controlling electrodes were arranged in a square, with the sensingelectrode at the center of he square. One pair of controlling electrodescomprised an electrode at the apex of the left ventricle and anelectrode at the base. The other two electrodes were located in thehalfway between the base and the apex of the left ventricle and near theright ventricle (at either side of the left ventricle). The appliedpulse was 10 mA for 20 msec at a delay of 2 msec. Both pairs ofelectrodes are electrified simultaneously.

In this experiment, an increase in the afterload and an increase inend-systolic LVP were observed. In addition, a decrease in end-diastolicLVP was observed. An increase in flow of about 7% is also shown in FIG.15.

FIG. 16 is a series of graphs showing experimental results from anotherexperiment, similar to the experiment of FIG. 14, except that no sensingelectrode is used. Rather, an activation signal propagation time isestimated for calculation of the desired delay between pacing the rightatrium and controlling the left atrium. The activation propagation timeis estimated by measuring the time between the pacing signal and thecontraction of the left ventricle. The delay time is 5 msec more thanthe calculated average propagation time and was about 140 msec. In thisexperiment, an increase in the afterload and an increase in LVP wereobserved. An increase in flow of about 14% is also shown in FIG. 16.

FIG. 17 is a series of graphs showing experimental results from anotherexperiment, similar to the experiment of FIG. 14, except that no pacingelectrodes are used. Rather, the isolated heart is allowed to pace atits own rhythm. The pulse parameters are a 20 msec long pulse of 10 mAapplied to both pairs of electrodes simultaneously, at a delay of 2 msecafter the sensing electrode senses a local activation potential.

In this experiment, an increase in the afterload and an increase in LVPwere observed. An increase in flow of about 7% is also shown in FIG. 17.It should be noted that the baseline output of the heart was about 110ml/min, which indicates an output of a healthy heart.

FIG. 18A is a series of graphs showing experimental results from anotherexperiment in which the heart was made ischemic. The wiring is similarto that of FIG. 17, except that only one pair of controlling electrodeswas used, one at the apex and one at the base of the left ventricle. Theischemia was designed to simulate a heart attack by stopping the flow ofoxygenated solution to the coronary arteries for about ten minutes.After the flow of oxygenated solution was restarted a reduction in thecardiac output from 100 ml/min. to 38 ml/min. was observed. In addition,various arrhythmias in the activation of the heart were observed as aresult of the ischemic incident. Controlling the heart, using a 20 msecpulse of 5 mA delayed 2 msec after the pacing, increased the flow by16%. The sensing was blocked for between 100 and 200 msec after thesensing of a local activation. It should be noted that the controllingsequence worked even though the heart was arrhythmic.

One interesting result of the isolated heart experiments relates topulse forms which do not induce fibrillation in the heart. It wasdetermined that the pulse should not extend more than about half theduration of the left ventricle pressure wave (in this experimentalsetup, the pressure wave is measured, not electrical activity). Inaddition, a small delay (˜5 msec) between the pacing and the pulse alsoappears to protect against fibrillation when the left ventricle ispaced.

FIG. 18B is a series of graphs showing experimental results from anotherexperiment in which the output of the heart was reduced. The heart waspaced at the right atrium, using a pacing scheme similar to that of theexperiment of FIG. 14. A controlling current was applied to the leftventricle using carbon electrodes. The controlling current was a 20 msecpulse of 5 mA amplitude applied at a delay of 30 msec after the pacingat the right atrium. Flow, LVP and Aortic pressure were all noticeablyreduced as a result of this pulse.

Reducing the cardiac output is desirable in several circumstances, oneof which is the disease “Hyperthropic Cardiomyopathy (HOCM).” Thiscontrolling scheme reduces the output of the left ventricle and theresistance against which the left ventricle is working, both of whichare desirable for the above disease. It is hypothesized that the earlycontrolling pulse (it is applied before the activation front from theright atrium reaches the left ventricle) works by extending therefractory periods of some of the cells in the left ventricle, therebyreducing the number of cells which take part in the systole and reducingthe cardiac output. Presumably, different cells are affected eachcardiac cycle. Alternatively, it may be that the precise delaydetermines which cells are affected. It is known to shorten the AVinterval in order to improve the conditions of patients with HOCM.However, in the art, the entire ventricle is paced, albeit earlier. Inthe embodiment of the invention just described, the early appliedelectric filed does not an early contraction of the ventricle, and doesnot effectively shorten the AV interval, as done in the art.

FIGS. 19 and 20 show the results of experiments performed on liveanimals on an in-vivo heart. In the experiment whose results are shownin FIG. 19, a live 2.5 Kg rabbit was anesthetized using a venous accessin its pelvic region with its chest opened to expose the heart. Thepericardium of the heart was removed to provide direct contact betweenthe heart and electrodes. The heart was paced via the left ventricleusing a pair of titanium electrodes and the controlling current wasapplied using a pair of carbon electrodes. As in previous experiments,the pacing was applied at the apex of the left ventricle and thecontrolling electrodes were applied one at the base and one at the apexof the left ventricle. The rabbit was artificially respirated andliquids were supplied through the venous access. A blood-pressurecatheter was inserted into the left femoral artery to measure thearterial blood pressure. The right carotid artery was exposed and amagnetic flowmeter was placed thereon to measure the flow in the carotidartery. The flow in a carotid artery was measured rather than the flowin the aorta for reasons of convenience. However, it should be notedthat the carotid arteries have a feedback mechanism by which theyattempt to maintain a constant blood supply to the brain by contractingthe artery if the flow is too high.

The controlling signal was a 40 msec pulse having a amplitude of 4 mAand applied 5 msec after the pacing signal. The pacing signal was a 2msec, 2 mA pulse at 5 Hz. An increase in flow in the right carotidartery of between 54 and 72% was observed during the application of thecontrolling signal.

The experiment whose results are shown in FIG. 20 had a similar designto the experiment of FIG. 19, except that the flow was measured using anultrasonic flowmeter. The controlling current was a 20 msec pulse havingan amplitude of 2 mA and delayed 5 msec from the pacing signal (whichwas the same as in the experiment of FIG. 19). Both an increase in flowand in blood pressure were observed in this experiment.

FIG. 21 shows the results of an experiment in an in-vivo he in which theheart was not paced. It is similar to the experiments of FIGS. 19 and20, in that blood pressure was measured in the right femoral artery andflow was measured, using an ultrasonic flowmeter, through the rightcarotid artery. The controlling pulse was applied using titanium-nitrideelectrodes, at the apex and at the base of the left ventricle. Aniridium-platinum bi-polar electrode was placed at the apex of the leftventricle to sense the arrival of an activation front from the SA nodeof the heart. The controlling current was a 20 msec pulse, having anamplitude of 2 mA and applied 30 msec after the activation front wassensed. Increases in both the blood flow and the blood pressure wereobserved in this experiment.

FIGS. 22 and 23 show the results of two experiments, similar to theexperiment of FIG. 21, in which the flow parameter was measured on theascending aorta. The heart of a 1.1 Kg rabbit was exposed and a sensingelectrode (bipolar) was inserted, using a needle, into the apex of theheart. Two carbon electrodes were used to apply a controlling pulse tothe heart, at the apex and the base of the left ventricle. The heart wasnot paced, it intrinsic pace was about 5 Hz. The control pulse was a 5mA in amplitude and had a duration of 40 msec. There was no delaybetween the sensing of an activation front at the sensing electrodes andapplication of the pulse.

FIG. 22 shows an increase of about 11% in the aortic flow. FIG. 23,which shows the results of a repetition of the same experiment on thesame animal at a later time, shows an increase of about 8%.

Although the present invention has been described mainly with referenceto the heart, it should be appreciated that preferred embodiments of thepresent invention may be applied to the types of excitable tissue. Inone example, skeletal muscle and smooth muscle can be controlled asdescribed hereinabove. It should however be appreciated, that mostmuscles have different ion channels and different resting potentialsthan cardiac muscle, so that the general principles must be adapted tothe individual physiology. In addition, the effects in a skeleton musclemay be due to recruitment of muscle fibers. Further, the presentinvention may be applied to neural tissue. For example, epileptic fitsand tetanization may be controlled by damping the excitability of neuraltissue, as described above. Alternatively, electrical control may beused in conjunction with electrical stimulation of denervated oratrophied muscles to increase the precision of stimulation. Additionallyor alternatively, electrical control may be used to block or enhanceconduction of stimuli along nervous pathways, for example, to controlpain.

In a preferred embodiment of the invention, epileptic fits arecontrolled by suppressing Golgi cells, thus, reducing the excitabilityof associated neural tissues by reducing the amount of availablecalcium.

The above description of the present invention focuses on electricalcontrol of cardiac tissue. However, since some aspect of the control maybe related to calcium ion transport in the cardiac tissue,non-electrical control is also possible. One major advantage ofnon-electrical control is that even though incorrect synchronization ofthe control to the cardiac cycle may reduce the cardiac output, there islittle or no danger of fibrillation. In one preferred embodiment of thepresent invention light is used to control calcium transport in portionsof the heart. Laser light may be used to affect the calcium transportdirectly. Alternatively, a light activated chelator, which is introducedinto at least some of he cells in a heart, may be activated by regularlight to change the availability (increasing or reducing) of calcium inthe illuminated cells. A controller in accordance with this embodimentof the invention, will include at least a light source and a lightguide, preferably an optical fiber, which will convey the light todesired portions of the heart. Preferably, the optical fiber is asilicon-rubber optical fiber which is resistant to breakage.Alternatively, the controller comprises a plurality of light emittingelements, such as laser diodes, placed directly on the controlledtissue. Further alternatively, the light is provided by a catheterinserted into the heart and either floating in the heart or fixed to theheart wall. The controller preferably includes an ECG sensor for sensinglocal and/or global activation times, as described above.

One limitation of light over electrical current is that unless the bodytissues are transparent to the particular wavelength used, light canonly have a very localized effect, a global effect requires many lightsources, which is invasive. One type of less invasive light source whichmay be useful is an optical fiber having a partially exposed sheath.Light will leak out of the fiber at the exposed portions, so a singlefiber can illuminate a plurality of localities.

In an alternative embodiment of the invention, electromagnetic radiationat low and/or radio frequencies is used to affect calcium transport inthe cardiac tissue. Several methods may be used to provideelectromagnetic radiation. In one method, the entire heart isirradiated, preferably in synchrony with a sensed ECG of the heart. Inanother method, a phased array is used to aim the radiation at theheart. As noted above, the non-arrhythmic heart substantially repeatsits position each cycle, so here is no problem of registration betweenan external source and a portion of the heart. In yet another method, animplanted device includes a plurality of antennas, each disposedadjacent to a portion of tissue to be controlled. The antennas may bepowered by a central source. Alternatively, the antenna are concentrateexternally applied radiation. Further alternatively, the antennas arecoils which generate localized AC magnetic fields. It should be notedthat electromagnetic radiation appears to be suitable for reducingcalcium availability, which makes it suitable for reducing the oxygendemands of an infarcted tissue after a heart attack. In embodimentsusing electromagnetic-radiation as in light and electric current, theremay be a long term reduction in the effectiveness of the controller dueto adaptation mechanisms of the heart. Thus, in a preferred embodimentof the invention, the controller is not used continuously, withpreferred rest periods between uses, being minutes, hours, days or weeksdepending on the adaptation of the heart.

In a preferred embodiment of the invention, two or more controlmodalities are applied simultaneously, for example, applying both lightradiation and electric fields. Alternatively, these modalities may beapplied alternately, so as to cope with adaptation mechanisms.Preferably, each modality is applied until adaptation sets in, at whichpoint the modality is switched.

Although the present invention has been described using a limited numberof preferred to embodiments, it should be appreciated that it is withinthe scope of the invention to combine various embodiments, for example,increasing the contractility of the left ventricle, while controllingthe heart rate in the right atrium. It is also in the scope of thepresent invention to combine limitations from various embodiments, forexample, limitations of pulse duration and pulse delay relative to anactivation or limitations on electrode type and electrode size. Further,although not all the methods described herein are to be construed asbeing performed using dedicated or programmed controllers, the scope ofthe invention includes controllers which perform these methods. In somecases, limitations of preferred embodiments have been described usingstructural or functional language for clarity, however, the scope of theinvention includes applying these limitations to both apparatus andmethods.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has thus far been particularlydescribed. Rather, the present invention is limited only by the claimswhich follow.

1. A method of modifying an activity of a heart or of a portion thereof,the method comprising: applying to cardiac neural tissue which isnervous tissue contacting heart muscle an electric field of a magnitude,shape, duty cycle, phase, frequency, and duration suitable to obtain adesired change, to modify an activity of the heart or a portion thereof,wherein said field is applied at a time at which it is non-excitatoryand thereof unable to generate a propagating action potential in theheart muscle, wherein said field has a strength insufficient fordefibrillation the heart by synchronization of refractory andnon-refractory cells to which it is applied and wherein said field isapplied during an absolute refractory phase of cardiac muscle cells intissue adjacent said cardiac neural tissue an in synchrony withactivation thereof.
 2. A method according to claim 1, wherein thenon-excitatory electric field dampens excitability of neural tissue. 3.A method according to claim 1, wherein the non-excitatory electric fieldblocks conduction of stimuli along a neural pathway.
 4. A methodaccording to claim 1, wherein the non-excitatory electric field enhancesconduction of stimuli along a neural pathway.
 5. A method according toclaim 1, wherein the non-excitatory electric field reduces anexcitability of the cardiac neural tissue.
 6. A method according toclaim 5, the excitability of the cardiac neural tissue is reduced byreducing an amount of available calcium.
 7. A method according to claim1, comprising: monitoring an activity of the heart or a portion thereof;and adjusting the applying responsive to the monitoring.
 8. A methodaccording to claim 7, wherein the non-excitatory electric field dampensexcitability of neural tissue.
 9. A method according to claim 7, whereinthe non-excitatory electric field blocks conduction of stimuli along aneural pathway.
 10. A method according to claim 7, wherein thenon-excitatory electric field enhances conduction of stimuli along aneural pathway.
 11. A method according to claim 7, wherein thenon-excitatory electric field reduces an excitability of the cardiacneural tissue.
 12. A method according to claim 11, the excitability ofthe cardiac neural tissue is reduced by reducing an amount of availablecalcium.
 13. A method according to claim 1, comprising applying saidnon- excitatory electric field as a continuation of a pacing field. 14.A method according to claim 1, comprising also pacing said heart.
 15. Amethod according to claim 1, wherein said applying comprises applyingfor a plurality of non-contiguous beats with a plurality of non-appliedbeats between.
 16. A method according to claim 1, wherein said applyingcomprises applying with a magnitude greater than needed for pacing ofsaid heart.
 17. A method according to claim 1, wherein said applyingcomprises applying in a manner suitable for a desired effect ofincreasing stroke volume of said heart.
 18. A method according to claim1, wherein said applying comprises applying in a manner suitable for adesired effect of increasing cardiac output of said heart.
 19. A methodaccording to claim 1, wherein said applying comprises applying in amanner suitable for a desired effect of controlling heart rate.
 20. Amethod according to claim 19, wherein said applying comprises applyingin a manner suitable for a desired effect of reducing heart rate.
 21. Amethod according to claim 19, wherein said applying comprises applyingin a manner suitable for a desired effect of one or both of stoppingarrhythmia and preventing arrhythmia.
 22. A method according to claim 1,wherein said applying comprises applying said field at least 100 beatsout of 50,000 consecutive beats.
 23. A method according to claim 1,wherein said applying comprises applying said field at least 1000 beatsout of 50,000 consecutive beats.
 24. A method according to claim 1,wherein said applying comprises applying said field at least 4000 beatsout of 50,000 consecutive beats.
 25. A method according to claim 1,wherein said applying causes an increase in flow volume of at least 5%.26. A method according to claim 1, wherein said applying comprisesdetermining a state of reduced cardiac output and applying said field inresponse to said determining.
 27. A method according to claim 1,comprising, as part of an ongoing schedule of applying to a paced heartor a heart in a non-arrhythmic state, modifying said applying inresponse to feedback indicating cardiac output.
 28. A method accordingto claim 1, wherein said applying comprises applying said field forbetween 3 and 5000 consecutive beats.
 29. A method according to claim 1,wherein said applying comprises applying said field periodicallyaccording to a therapy schedule.
 30. A method according to claim 29,wherein said applying comprises applying said field on a daily basis.31. A method according to claim 1, wherein said applying causes anincrease in cardiac output.
 32. A method according to claim 1, whereinsaid applying causes an increase in contractility of at least 5%.
 33. Amethod according to claim 1, wherein said electric field has a frequencyselected to open some ion channels and not others.